Clinical Trials List
Protocol NumberGO29436
NCT Number(ClinicalTrials.gov Identfier)NCT02366143
2015-07-01 - 2019-12-16
Phase III
Terminated12
ICD-10C34
Malignant neoplasm of bronchus and lung
A Phase III, Open-Label, Randomized Study Of MPDL3280A (Anti-PD-L1 Antibody) In Combination With Carboplatin + Paclitaxel With Or Without Bevacizumab Compared With Carboplatin + Paclitaxel + Bevacizumab In Chemotherapy-Naïve Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer
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Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
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Sponsor
F. Hoffmann-La Roche Ltd
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Shah-Hwa Chou Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- JENG-SEN TSENG Division of Thoracic Medicine
- KUO-HSUAN HSU Division of Thoracic Medicine
- TSUNG -YING YANG Division of Thoracic Medicine
- 陳焜結 Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 黃子權 Division of Hematology & Oncology
- 葉人華 Division of Hematology & Oncology
- 張平穎 Division of Hematology & Oncology
- 蔡鎮良 Division of Hematology & Oncology
- 陳宇欽 Division of Hematology & Oncology
- 吳宜穎 Division of Hematology & Oncology
- 戴明燊 Division of Hematology & Oncology
- 陳佳宏 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 蕭丞皓 Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Wei-Pang Chung Division of Hematology & Oncology
- Shang-Yin Wu Division of Hematology & Oncology
- Wen-Pin Su Division of Hematology & Oncology
- Sin-Syue Li Division of Hematology & Oncology
- Yu-Min Yeh Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Co-Principal Investigator
- Wen-Cheng Chang Division of Hematology & Oncology
- 謝任富 Division of Radiology
- 林倡葦 Division of Hematology & Oncology
- 林定佑 Division of Hematology & Oncology
- Cheng-Ta Yang Division of Hematology & Oncology
- Shih-Hong Li Division of Hematology & Oncology
- Shih-Wei Lin Division of Hematology & Oncology
- 枋岳甫 Division of Hematology & Oncology
- Chih-Hung Chen Division of Hematology & Oncology
- Chih-Hung Chen Division of Hematology & Oncology
- 李忠恕 Division of Hematology & Oncology
- Chih-Liang Wang Division of Hematology & Oncology
- 莊立邦 Division of Hematology & Oncology
- 黃世豪 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Co-Principal Investigator
- Chen Chia-Hung Division of Thoracic Medicine
- 陳鴻仁 Division of Thoracic Medicine
- 廖偉志 Division of Thoracic Medicine
- Chih-Yen Tu Division of Thoracic Medicine
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- CHAO-CHI HO CHAO-CHI HO Division of Thoracic Medicine
- 陳冠宇 Division of Thoracic Medicine
- 林育麟 Division of Hematology & Oncology
- 許嘉林 Division of Thoracic Medicine
- 廖唯昱 Division of Thoracic Medicine
- Chia-Chi Lin Division of Hematology & Oncology
- Jih-Hsiang Lee Division of Hematology & Oncology
- JIN-YUAN SHIH Division of Thoracic Medicine
- James Chih-Hsin Yang Division of Hematology & Oncology
- 吳振都 Division of Others
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Non-Small Cell Lung Cancer (NSCLC)
Objectives
The co-primary objectives of this study are:
To evaluate the efficacy of MPDL3280A in the intent-to-treat (ITT) population as
measured by investigator-assessed progression-free survival (PFS) according to
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in each of the following two
treatment comparisons:
MPDL3280A +carboplatin + paclitaxel vs. carboplatin + paclitaxel + bevacizumab
MPDL3280A + carboplatin + paclitaxel + bevacizumab vs. carboplatin + paclitaxelv+ bevacizumab
To evaluate the efficacy of MPDL3280A in the programmed death-ligand 1 (PD-L1)
selected population as measured by investigator-assessed PFS according to RECIST
v1.1 in each of the two treatment comparisons described above
Test Drug
Atezolizumab (MPDL3280A)
Active Ingredient
MPDL3280A (anti-PD-L1 antibody)
Dosage Form
IV
Dosage
60mg/mL
Endpoints
Curative effect index
The efficacy targets will be compared and analyzed for the following two trials, unless otherwise stated:
- Atezolizumab carboplatin paclitaxel bevacizumab (group B) compared to carboplatin paclitaxel bevacizumab (group C)
- Atezolizumab carboplatin paclitaxel (group A) compared to carboplatin paclitaxel bevacizumab (group C)
The term "wild type" (WT) refers to randomly assigned patients without sensitive EGFR mutations or ALK translocations.
The term "Tumor Gene Expression" (tGE) refers to a random allocation of patients with the characteristics of T-acting sub-genes and that the level of PD-L1 expression in tumor tissues meets the definition according to the RNA test conducted by the central government.
According to the central IHC test, the PD-L1 performance of tumor cells (TC) and immune cells (IC) will meet the definition of randomly assigned populations to analyze some efficacy indicators.
The common main goals of this experiment are as follows:
To evaluate the efficacy of atezolizumab, the measurement method is that the trial host evaluates the disease-free survival (PFS) of the tGE-WT and ITT-WT groups according to the Solid Tumor Efficacy Evaluation Standard (RECIST) Version 1.1 (RECIST v1.1)
To evaluate the efficacy of atezolizumab, the measurement method is the overall survival (OS) of the ITT-WT population
The secondary efficacy goals of this trial are as follows:
To evaluate the efficacy of atezolizumab, the measurement method is the OS of the tGE WT population
To evaluate the efficacy of atezolizumab, the measurement method is based on the PFS and OS of the TC2/3 or IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population evaluated by the trial host based on RECIST Version 1.1
To evaluate the efficacy of atezolizumab, the measurement method is based on the PFS and OS evaluated by the trial host based on RECIST Version 1.1 for the tGE and ITT populations
To evaluate the efficacy of atezolizumab, the measurement method is based on the objective response rate (ORR) evaluated by the trial host in accordance with RECIST Version 1.1 for the tGE-WT and ITT-WT populations
To evaluate the efficacy of atezolizumab, the measurement method is the duration of response (DOR) obtained by the trial host in accordance with RECIST Version 1.1 on the tGE-WT and ITT-WT populations.
To evaluate the efficacy of atezolizumab, the measurement method is the Independent Review Facility (IRF) PFS obtained by evaluating the tGE-WT and ITT-WT populations in accordance with RECIST Version 1.1
To evaluate the OS rate of each treatment group after 1 year and 2 years for the tGE-WT and ITT-WT groups
To compare the efficacy of two treatment groups containing atezolizumab in group A and group B. The measurement method is based on the PFS and OS evaluated by the trial host in accordance with RECIST Version 1.1 for the tGE-WT and ITT-WT groups
To determine the impact of atezolizumab, the measurement method is that patients in the tGE-WT and ITT-WT groups report the elapsed time before the worsening of lung cancer symptoms such as cough, dyspnea (single and multiple subscales), chest pain, or arm/shoulder pain (TTD) ), using the European Organization for Research on Cancer Therapy (EORTC) Core Quality of Life Questionnaire 30 (QLQ-C30) and Lung Cancer Supplementary Questionnaire (QLQ LC13)
To determine the impact of atezolizumab, the measurement method is to report lung cancer symptoms (chest pain, dyspnea, and cough) of patients in the tGE-WT and ITT-WT populations. Base period changes (that is, based on the existing symptoms as improved or worsened), and lung cancer symptoms are used (SILC) Scale symptom severity score.
Security goal
The safety goals of this test are as follows:
Evaluate the safety and tolerability of atezolizumab in each of the two treatment comparisons.
To evaluate the incidence and titer of anti-therapeutic antibodies (ATA) for atezolizumab, and to explore the possible relationship between immune response and pharmacokinetics, safety and efficacy.
Pharmacokinetic goals
The pharmacokinetic (PK) goals of this trial are as follows:
Under the concurrent use of atezolizumab, carboplatin and paclitaxel with or without bevacizumab (groups A and B), the pharmacokinetic properties of atezolizumab are summarized.
Under the concurrent use of carboplatin and paclitaxel with or without atezolizumab and/or bevacizumab (groups A, B, and C), summarize the pharmacokinetic properties of carboplatin.
Under the concurrent use of paclitaxel and carboplatin with or without atezolizumab and/or bevacizumab (groups A, B, and C), the pharmacokinetics of paclitaxel was summarized characteristic.
Under the simultaneous use of bevacizumab, carboplatin, and paclitaxel with or without atezolizumab (groups B and C), summarize the pharmacokinetic properties of bevacizumab.
Exploratory goal
The exploratory goals of this experiment are as follows:
- To evaluate the efficacy of atezolizumab, the measurement method is based on the time to response (TTR) and time to response (TIR) evaluated by the trial host according to RECIST Version 1.1
- ORR and DOR evaluated by IRF based on RECIST Version 1.1.
- The ORR, PFS and DOR of the atezolizumab treatment group evaluated by the trial host according to the revised RECIST evaluation.
- Assess the PFS of each treatment group at 6 months and 1 year
- Assess the 3-year OS rate of each treatment group
- Assess the predictive, diagnostic, and exploratory biological indicators of drug efficacy in archives and/or fresh tumor tissues and blood, as well as the correlation between these indicators and disease conditions, drug resistance mechanisms, and/or experimental treatment responses.
- The evaluation is carried out with biopsies when the disease is obvious, and it is used to distinguish the significant increase in tumor volume caused by the immunomodulatory activity of atezolizumab (ie pseudo-progression/tumor immune infiltration) and the real disease progression.
- The health status of patients obtained by the European Quality of Life Scale Five-Oriented Three-Level Questionnaire (EQ-5D 3L) is compared and compared, and the application score of the benefit economic model is constructed with this information.
- To evaluate the impact of atezolizumab, the measurement method informs patients of health-related quality of life results, lung cancer-related symptoms, and the amount of change from the baseline value of the functional results measured by EORTC QLQ-C30 and LC13.
The efficacy targets will be compared and analyzed for the following two trials, unless otherwise stated:
- Atezolizumab carboplatin paclitaxel bevacizumab (group B) compared to carboplatin paclitaxel bevacizumab (group C)
- Atezolizumab carboplatin paclitaxel (group A) compared to carboplatin paclitaxel bevacizumab (group C)
The term "wild type" (WT) refers to randomly assigned patients without sensitive EGFR mutations or ALK translocations.
The term "Tumor Gene Expression" (tGE) refers to a random allocation of patients with the characteristics of T-acting sub-genes and that the level of PD-L1 expression in tumor tissues meets the definition according to the RNA test conducted by the central government.
According to the central IHC test, the PD-L1 performance of tumor cells (TC) and immune cells (IC) will meet the definition of randomly assigned populations to analyze some efficacy indicators.
The common main goals of this experiment are as follows:
To evaluate the efficacy of atezolizumab, the measurement method is that the trial host evaluates the disease-free survival (PFS) of the tGE-WT and ITT-WT groups according to the Solid Tumor Efficacy Evaluation Standard (RECIST) Version 1.1 (RECIST v1.1)
To evaluate the efficacy of atezolizumab, the measurement method is the overall survival (OS) of the ITT-WT population
The secondary efficacy goals of this trial are as follows:
To evaluate the efficacy of atezolizumab, the measurement method is the OS of the tGE WT population
To evaluate the efficacy of atezolizumab, the measurement method is based on the PFS and OS of the TC2/3 or IC2/3 WT population and the TC1/2/3 or IC1/2/3 WT population evaluated by the trial host based on RECIST Version 1.1
To evaluate the efficacy of atezolizumab, the measurement method is based on the PFS and OS evaluated by the trial host based on RECIST Version 1.1 for the tGE and ITT populations
To evaluate the efficacy of atezolizumab, the measurement method is based on the objective response rate (ORR) evaluated by the trial host in accordance with RECIST Version 1.1 for the tGE-WT and ITT-WT populations
To evaluate the efficacy of atezolizumab, the measurement method is the duration of response (DOR) obtained by the trial host in accordance with RECIST Version 1.1 on the tGE-WT and ITT-WT populations.
To evaluate the efficacy of atezolizumab, the measurement method is the Independent Review Facility (IRF) PFS obtained by evaluating the tGE-WT and ITT-WT populations in accordance with RECIST Version 1.1
To evaluate the OS rate of each treatment group after 1 year and 2 years for the tGE-WT and ITT-WT groups
To compare the efficacy of two treatment groups containing atezolizumab in group A and group B. The measurement method is based on the PFS and OS evaluated by the trial host in accordance with RECIST Version 1.1 for the tGE-WT and ITT-WT groups
To determine the impact of atezolizumab, the measurement method is that patients in the tGE-WT and ITT-WT groups report the elapsed time before the worsening of lung cancer symptoms such as cough, dyspnea (single and multiple subscales), chest pain, or arm/shoulder pain (TTD) ), using the European Organization for Research on Cancer Therapy (EORTC) Core Quality of Life Questionnaire 30 (QLQ-C30) and Lung Cancer Supplementary Questionnaire (QLQ LC13)
To determine the impact of atezolizumab, the measurement method is to report lung cancer symptoms (chest pain, dyspnea, and cough) of patients in the tGE-WT and ITT-WT populations. Base period changes (that is, based on the existing symptoms as improved or worsened), and lung cancer symptoms are used (SILC) Scale symptom severity score.
Security goal
The safety goals of this test are as follows:
Evaluate the safety and tolerability of atezolizumab in each of the two treatment comparisons.
To evaluate the incidence and titer of anti-therapeutic antibodies (ATA) for atezolizumab, and to explore the possible relationship between immune response and pharmacokinetics, safety and efficacy.
Pharmacokinetic goals
The pharmacokinetic (PK) goals of this trial are as follows:
Under the concurrent use of atezolizumab, carboplatin and paclitaxel with or without bevacizumab (groups A and B), the pharmacokinetic properties of atezolizumab are summarized.
Under the concurrent use of carboplatin and paclitaxel with or without atezolizumab and/or bevacizumab (groups A, B, and C), summarize the pharmacokinetic properties of carboplatin.
Under the concurrent use of paclitaxel and carboplatin with or without atezolizumab and/or bevacizumab (groups A, B, and C), the pharmacokinetics of paclitaxel was summarized characteristic.
Under the simultaneous use of bevacizumab, carboplatin, and paclitaxel with or without atezolizumab (groups B and C), summarize the pharmacokinetic properties of bevacizumab.
Exploratory goal
The exploratory goals of this experiment are as follows:
- To evaluate the efficacy of atezolizumab, the measurement method is based on the time to response (TTR) and time to response (TIR) evaluated by the trial host according to RECIST Version 1.1
- ORR and DOR evaluated by IRF based on RECIST Version 1.1.
- The ORR, PFS and DOR of the atezolizumab treatment group evaluated by the trial host according to the revised RECIST evaluation.
- Assess the PFS of each treatment group at 6 months and 1 year
- Assess the 3-year OS rate of each treatment group
- Assess the predictive, diagnostic, and exploratory biological indicators of drug efficacy in archives and/or fresh tumor tissues and blood, as well as the correlation between these indicators and disease conditions, drug resistance mechanisms, and/or experimental treatment responses.
- The evaluation is carried out with biopsies when the disease is obvious, and it is used to distinguish the significant increase in tumor volume caused by the immunomodulatory activity of atezolizumab (ie pseudo-progression/tumor immune infiltration) and the real disease progression.
- The health status of patients obtained by the European Quality of Life Scale Five-Oriented Three-Level Questionnaire (EQ-5D 3L) is compared and compared, and the application score of the benefit economic model is constructed with this information.
- To evaluate the impact of atezolizumab, the measurement method informs patients of health-related quality of life results, lung cancer-related symptoms, and the amount of change from the baseline value of the functional results measured by EORTC QLQ-C30 and LC13.
Inclution Criteria
Inclusion conditions
Patients must meet all of the following conditions to be included in this trial:
1. Sign the subject consent form
2. Male or female who is over 18 years old (patients participating in this trial in Taiwan must be over 20 years old)
3. United States East Coast Cancer Clinical Research Cooperative (ECOG) physical status 0 or 1.
4. Stage 4 non-squamous non-small cell lung cancer confirmed by histology or cytology (according to the United International Cancer Center [Union Internationale contre le Cancer]/American Joint Committee on Cancer [American Joint Committee on Cancer] staging system, seventh edition ; Detterbeck et al., 2009)
If the main histology is shown to be non-squamous, patients with mixed histology (ie, squamous and non-squamous) are eligible.
5. Untreated fourth-stage non-squamous non-small cell lung cancer.
Patients with epidermal growth factor receptor (EGFR) gene sensitivity mutations must have experienced disease progression (during or after treatment), or received one or more EGFR TKIs (such as erlotinib, Aretha) (gefitinib)) or another EGFR TKI suitable for the treatment of EGFR mutant non-small cell lung cancer.
Patients with ALK fusion oncogene must have experienced disease progression (during or after treatment), or patients with non-small cell lung cancer with ALK fusion oncogene must receive one or more suitable ALK inhibitor drugs (ie cut-off An intolerable condition occurs after crizotinib.
If the patient's EGFR and/or ALK status is unknown, the test results need to be provided during screening. ALK and/or EGFR can be evaluated in local or central laboratories.
6. If the patient has received new adjuvant therapy, adjuvant chemotherapy, radiotherapy or chemoradiation therapy for curing non-metastatic diseases, the patient must pass between the latest chemotherapy, radiotherapy or chemoradiation therapy and random assignment. A treatment-free period of at least 6 months.
7. Patients with a history of treatment of asymptomatic CNS metastasis are considered eligible, provided that the following conditions are met:
Only the supratentorial and cerebellar metastases (ie no metastases in the midbrain, pons, medulla oblongata or spinal cord) are allowed.
There is no need to treat central nervous system diseases with corticosteroids.
If you did not receive stereotactic radiotherapy within 7 days before random assignment, the whole brain radiation was within 14 days.
No evidence of interim progress during the completion of CNS-directed therapy and screening radiology trials.
When a new asymptomatic CNS metastasis is found by a screening scan, the patient must receive radiotherapy and/or surgery for the CNS metastasis. After treatment, if these patients meet all other conditions, they may be eligible without additional brain scans before randomization.
8. The central laboratory will perform immunohistochemical staining (IHC) on the previously obtained archived tumor tissue or the biopsy during screening to determine the known PD-L1 tumor status.
To participate in this trial, a typical formalin fixed paraffin-embedded (FFPE) tumor specimen paraffin block (recommended) or 15 or more unstained serial slides freshly cut from the FFPE tumor specimen is required. If fewer than 15 slides (but not less than 10) are available during the base period, the patient can still be eligible after discussion with the medical monitor. This specimen must be accompanied by a relevant pathology report.
Fine needle aspiration (defined as a specimen that does not preserve tissue structure and is not used to make cell suspensions and/or cell smears), brushing or sedimenting cells (for example: taken from pleural effusion and lavage specimens) Not accepted.
Bone metastasis tumor tissue taken from decalcification is not accepted.
For thick needle biopsy, it is recommended that at least three thick needle samples be embedded in a single paraffin block and sent for evaluation.
9. According to RECIST (Solid Tumor Response Evaluation Criteria) Version 1.1, it is defined as a measurable disease.
If the lesions that have received radiation have clearly recorded that the disease has deteriorated since the radiotherapy, and the lesions that have received radiation are not the only part of the disease, they are regarded as measurable diseases.
10. The following test results were obtained in the 14 days before random assignment, which showed that the blood and peripheral organs were adequate:
In the absence of granular leukocyte stimulating factor, neutrophils 1500/L
Lymphocyte count 500/L
Platelet count 100,000/L (without blood transfusion)
Heme 9.0 g/dL
Patients can meet this condition by receiving blood transfusions.
International Normalized Ratio (INR) or Partial Coagulation Time (aPTT) 1.5 times the upper limit of normal (ULN).
This condition is only applicable to those who have not received anticoagulation therapy, and patients receiving anticoagulation therapy should maintain a stable dose.
Aspartate transamidation (AST), alanine transamidation (ALT) and alkaline phosphoric acid 2.5 times the upper limit of normal, with the following exceptions:
Patients with known liver metastases: AST and/or ALT 5 times the upper limit of normal
Cases showing patients with liver or bone cancer metastasis: alkaline phosphate; 5 times the upper limit of normal.
Serum bilirubin 1.25 times the upper limit of normal
Patients with known Gilbert's disease and those with serum bilirubin 3 times the upper limit of normal can be included in the trial.
Serum creatinine 1.5 times the upper limit of normal
11. For female patients with fertility, it should be agreed (by the patient and/or their partner) to adopt a contraceptive method that is highly effective and continues to be used in the correct way, with a very low failure rate (<1% per year). And continue to use this contraceptive method for 5 months after the last dose of atezolizumab and/or continue to use this contraceptive method for 6 months after receiving the last dose of bevacizumab or paclitaxel, whichever occurs later) . Women are not allowed to donate eggs during this same period. Highly effective contraceptive methods include: compound (containing estrogen and progesterone) hormonal contraceptives, oral contraceptives containing only progesterone for inhibiting ovulation, and another barrier method containing spermicides, intrauterine contraceptive devices (IUD), Intrauterine administration system (IUS), bilateral tubal ligation, partner vasectomy (based on only one partner during the entire trial period), and abstinence.
12. For male patients whose female partners are fertile, it should be agreed (by the patient and/or their partners) to adopt a contraceptive method that is highly effective and continues to be used in the correct way, with a very low failure rate (<1% per year) Method, and continue to use this contraceptive method for 6 months after receiving the last dose of atezolizumab, carboplatin or paclitaxel. Male patients should not donate sperm during the trial and at least 6 months after receiving the last dose of bevacizumab, carboplatin or paclitaxel.
13. Oral contraceptives must be combined with other contraceptive methods, because oral contraceptives and test drugs may have potential interactions. If the partner of a male patient participating in this clinical trial is fertile, the same rules apply to male patients participating in this clinical trial. Male patients must use condoms.
14. In the 14 days before starting to use the test drug, women who have not menopause (non-treatment-induced amenorrhea lasting 12 months) or surgically sterilized women must undergo a serum pregnancy test to obtain a negative result.
Patients must meet all of the following conditions to be included in this trial:
1. Sign the subject consent form
2. Male or female who is over 18 years old (patients participating in this trial in Taiwan must be over 20 years old)
3. United States East Coast Cancer Clinical Research Cooperative (ECOG) physical status 0 or 1.
4. Stage 4 non-squamous non-small cell lung cancer confirmed by histology or cytology (according to the United International Cancer Center [Union Internationale contre le Cancer]/American Joint Committee on Cancer [American Joint Committee on Cancer] staging system, seventh edition ; Detterbeck et al., 2009)
If the main histology is shown to be non-squamous, patients with mixed histology (ie, squamous and non-squamous) are eligible.
5. Untreated fourth-stage non-squamous non-small cell lung cancer.
Patients with epidermal growth factor receptor (EGFR) gene sensitivity mutations must have experienced disease progression (during or after treatment), or received one or more EGFR TKIs (such as erlotinib, Aretha) (gefitinib)) or another EGFR TKI suitable for the treatment of EGFR mutant non-small cell lung cancer.
Patients with ALK fusion oncogene must have experienced disease progression (during or after treatment), or patients with non-small cell lung cancer with ALK fusion oncogene must receive one or more suitable ALK inhibitor drugs (ie cut-off An intolerable condition occurs after crizotinib.
If the patient's EGFR and/or ALK status is unknown, the test results need to be provided during screening. ALK and/or EGFR can be evaluated in local or central laboratories.
6. If the patient has received new adjuvant therapy, adjuvant chemotherapy, radiotherapy or chemoradiation therapy for curing non-metastatic diseases, the patient must pass between the latest chemotherapy, radiotherapy or chemoradiation therapy and random assignment. A treatment-free period of at least 6 months.
7. Patients with a history of treatment of asymptomatic CNS metastasis are considered eligible, provided that the following conditions are met:
Only the supratentorial and cerebellar metastases (ie no metastases in the midbrain, pons, medulla oblongata or spinal cord) are allowed.
There is no need to treat central nervous system diseases with corticosteroids.
If you did not receive stereotactic radiotherapy within 7 days before random assignment, the whole brain radiation was within 14 days.
No evidence of interim progress during the completion of CNS-directed therapy and screening radiology trials.
When a new asymptomatic CNS metastasis is found by a screening scan, the patient must receive radiotherapy and/or surgery for the CNS metastasis. After treatment, if these patients meet all other conditions, they may be eligible without additional brain scans before randomization.
8. The central laboratory will perform immunohistochemical staining (IHC) on the previously obtained archived tumor tissue or the biopsy during screening to determine the known PD-L1 tumor status.
To participate in this trial, a typical formalin fixed paraffin-embedded (FFPE) tumor specimen paraffin block (recommended) or 15 or more unstained serial slides freshly cut from the FFPE tumor specimen is required. If fewer than 15 slides (but not less than 10) are available during the base period, the patient can still be eligible after discussion with the medical monitor. This specimen must be accompanied by a relevant pathology report.
Fine needle aspiration (defined as a specimen that does not preserve tissue structure and is not used to make cell suspensions and/or cell smears), brushing or sedimenting cells (for example: taken from pleural effusion and lavage specimens) Not accepted.
Bone metastasis tumor tissue taken from decalcification is not accepted.
For thick needle biopsy, it is recommended that at least three thick needle samples be embedded in a single paraffin block and sent for evaluation.
9. According to RECIST (Solid Tumor Response Evaluation Criteria) Version 1.1, it is defined as a measurable disease.
If the lesions that have received radiation have clearly recorded that the disease has deteriorated since the radiotherapy, and the lesions that have received radiation are not the only part of the disease, they are regarded as measurable diseases.
10. The following test results were obtained in the 14 days before random assignment, which showed that the blood and peripheral organs were adequate:
In the absence of granular leukocyte stimulating factor, neutrophils 1500/L
Lymphocyte count 500/L
Platelet count 100,000/L (without blood transfusion)
Heme 9.0 g/dL
Patients can meet this condition by receiving blood transfusions.
International Normalized Ratio (INR) or Partial Coagulation Time (aPTT) 1.5 times the upper limit of normal (ULN).
This condition is only applicable to those who have not received anticoagulation therapy, and patients receiving anticoagulation therapy should maintain a stable dose.
Aspartate transamidation (AST), alanine transamidation (ALT) and alkaline phosphoric acid 2.5 times the upper limit of normal, with the following exceptions:
Patients with known liver metastases: AST and/or ALT 5 times the upper limit of normal
Cases showing patients with liver or bone cancer metastasis: alkaline phosphate; 5 times the upper limit of normal.
Serum bilirubin 1.25 times the upper limit of normal
Patients with known Gilbert's disease and those with serum bilirubin 3 times the upper limit of normal can be included in the trial.
Serum creatinine 1.5 times the upper limit of normal
11. For female patients with fertility, it should be agreed (by the patient and/or their partner) to adopt a contraceptive method that is highly effective and continues to be used in the correct way, with a very low failure rate (<1% per year). And continue to use this contraceptive method for 5 months after the last dose of atezolizumab and/or continue to use this contraceptive method for 6 months after receiving the last dose of bevacizumab or paclitaxel, whichever occurs later) . Women are not allowed to donate eggs during this same period. Highly effective contraceptive methods include: compound (containing estrogen and progesterone) hormonal contraceptives, oral contraceptives containing only progesterone for inhibiting ovulation, and another barrier method containing spermicides, intrauterine contraceptive devices (IUD), Intrauterine administration system (IUS), bilateral tubal ligation, partner vasectomy (based on only one partner during the entire trial period), and abstinence.
12. For male patients whose female partners are fertile, it should be agreed (by the patient and/or their partners) to adopt a contraceptive method that is highly effective and continues to be used in the correct way, with a very low failure rate (<1% per year) Method, and continue to use this contraceptive method for 6 months after receiving the last dose of atezolizumab, carboplatin or paclitaxel. Male patients should not donate sperm during the trial and at least 6 months after receiving the last dose of bevacizumab, carboplatin or paclitaxel.
13. Oral contraceptives must be combined with other contraceptive methods, because oral contraceptives and test drugs may have potential interactions. If the partner of a male patient participating in this clinical trial is fertile, the same rules apply to male patients participating in this clinical trial. Male patients must use condoms.
14. In the 14 days before starting to use the test drug, women who have not menopause (non-treatment-induced amenorrhea lasting 12 months) or surgically sterilized women must undergo a serum pregnancy test to obtain a negative result.
Exclusion Criteria
General medical exclusion
1. Women who are pregnant, breastfeeding, or intend to become pregnant during the trial period.
2. Had severe allergies, systemic allergies or other allergic reactions to chimeric/human-derived antibodies or fusion proteins.
3. Known to be allergic or allergic to the biopharmaceuticals produced by Chinese hamster ovary cells or any ingredients in the atezolizumab formula.
4. Have had autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome related vascular embolism, Wegener's granulomatosis (Wegener's granulomatosis), Sjogren's syndrome (Sjö gren's syndrome), Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis.
Patients with autoimmune hypothyroidism and receiving stable doses of thyroxine supplementation are eligible for this trial.
Patients with well-controlled type 1 diabetes who receive insulin at a stable dose are deemed eligible for this trial.
Patients with leukoplakia who only suffer from eczema, psoriasis, chronic lichen simplex, or only skin disease manifestations (for example, patients with psoriatic arthritis will be excluded) are considered eligible, provided that the following conditions are met:
The rash coverage must be less than 10% of the body surface area (BSA)
The disease is well controlled at the base stage, and only inefficient topical steroids are used
Existing conditions have no acute attacks in the past 12 months (no PUVA therapy [psoralen plus ultraviolet radiation], methotrexate, retinoids, biological agents, oral calcineurin; inhibitors, highly effective Or oral steroids)
5. With a history of spontaneous pulmonary fibrosis, organic pneumonia (bronchiolitis obliterans), drug-induced pneumonia, spontaneous pneumonia, or evidence of acute pneumonia found on a chest computer tomography during screening.
A history of radiation pneumonitis (fibrosis) at the radiotherapy site is permissible.
6. The human immunodeficiency virus (HIV) test result is positive.
All patients will be tested for HIV before being included in the trial; patients with positive HIV test results will not be able to participate in the trial.
7. Patients with acute or chronic hepatitis B and the hepatitis B surface antigen [HBsAg] test result is positive at the time of screening, or patients with hepatitis C.
Patients who have been infected with hepatitis B virus (HBV) or have remission of HBV infection (defined as hepatitis B core antibody [HBcAb] positive and hepatitis B surface antigen [HBsAg] negative) must be HBV DNA negative before they can be regarded as Qualified.
Hepatitis C virus (HCV) antibody-positive patients will be considered eligible only when the polymerized酶 chain reaction (PCR) test shows that hepatitis C virus ribonucleic acid is negative.
8. Active tuberculosis.
9. Serious infections occurred within 4 weeks before random assignment, including but not limited to hospitalization due to infection, bacteremia, or severe pneumonia complications.
10. Have received therapeutic oral or intravenous antibiotics within 2 weeks before random assignment.
Patients who have received prophylactic antibiotics (for example, to prevent urinary tract infections or prevent acute onset of chronic obstructive pulmonary disease) are considered eligible.
11. Major cardiovascular diseases, such as heart disease or cardiovascular accident (level 2 or above) as defined by the New York Heart Association, myocardial infarction, unstable arrhythmia, or unstable angina in the 3 months before random assignment .
Patients who are known to have coronary artery disease, congestive heart failure (but do not meet the above conditions), or left ventricular ejection fraction 50%, must stably receive the best course of treatment identified by the treating physician, and referral should be made when circumstances permit Cardiologist.
12. Randomly assign patients who have undergone major surgical procedures other than diagnosis within the previous 28 days, or are expected to undergo major surgery during the trial period
13. Have received allogeneic bone marrow transplantation or solid organ transplantation.
14. Vaccine live attenuated vaccine within 4 weeks before random assignment, or expect to be vaccinated with live attenuated vaccine during the trial period.
15. The existence of any other diseases, abnormal metabolic function, physical examination findings or clinical laboratory findings can reasonably suspect a certain disease or medical condition, which may make it impossible to use the test drug or may affect the interpretation of the test results, Or increase the patient’s risk of drug complications
16. The patient’s disease or condition will affect his or her ability to understand, follow, and/or follow the test procedures
Drug-related exclusions
1. Receive any approved anti-cancer therapy, including hormonal therapy, within 3 weeks before starting the trial treatment, except for the following conditions:
TKIs (tyrosine inhibitors) approved for the treatment of non-small cell lung cancer have been discontinued for more than 7 days before random assignment. Baseline scans must be performed after stopping the previous TKIs (tyrosine stimulants酶 inhibitors).
2. Receiving other experimental drug treatments with the intent of treatment within 28 days before random assignment.
3. Previously received CD137 agonist or immune checkpoint blocking therapy, anti-PD-1 and anti-PD-L1 therapeutic antibodies.
Patients who have previously received anti-CTLA-4 therapy can be included, provided they meet the following requirements:
It has been at least 6 weeks since receiving the last dose of anti-CTLA-4 before random assignment.
After receiving anti-CTLA-4, no severe immune indirect adverse effects (NCI CTCAE level 3 or 4)
4. Have received systemic immunostimulants (including but not limited to interferon, interleukin-2) within 4 weeks before random assignment or within the five half-life period of the drug (whichever is longer).
It is permissible to have received cancer vaccine before.
5. Received systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents [anti-TNF] within 2 weeks before random assignment ])treatment.
Patients who have received acute, low-dose (oral cortisol [prednisone] 10 mg or equivalent drugs), systemic immunosuppressive drugs, can participate in the trial.
Use of corticosteroids for chronic obstructive pulmonary disease (oral cortisol [prednisone] 10 mg or equivalent), use of mineral cortisol (eg fludrocortisone) for postural hypotension, and use of low doses for lack of adrenal cortex function Corticosteroid supplements are permissible.
Exclusions related to Bevacizumab
1. Poorly controlled hypertension (defined as systolic blood pressure 150 mmHg and/or diastolic blood pressure 100 mmHg)
It is permissible to use antihypertensive therapy to achieve these parameters.
2. With a history of hypertensive crisis or hypertensive encephalopathy
3. Experienced major vascular disease in the 6 months prior to random assignment (for example: aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis).
4. Haemorrhage occurred within 1 month before random assignment ( 2.5 mL of blood each time)
5. Evidence of hemorrhagic constitution or coagulopathy (not receiving anticoagulant treatment).
6. Currently or recently (within 10 days before random assignment) aspirin (325 mg per day), or dipyramidole, ticlopidine, clopidogrel or cilostazol.
7. A full dose of oral or injectable anticoagulant or thrombolytic agent is being used for treatment, but it has not stabilized within 2 weeks before randomization.
As long as the INR and aPTT are within the treatment limits (according to the medical standards of the receiving institution), and the patient is using the anticoagulant at a stable dose for at least 2 weeks before randomization, the oral or injection anticoagulant will be used according to the full dose It is the condition with permission.
Preventive anticoagulants used to maintain the patency of the venous access device in the 14 days prior to random assignment are permissible, but the result of the drug activity is INR 1.5 times the upper limit of normal and aPTT is within the normal range.
The use of preventive low molecular weight heparin (for example: enoxaparin, 40 mg per day) is permissible.
8. Have received a thick needle biopsy or other minor surgery within 7 days before receiving the first dose of bevacizumab, but the placement of the vascular access device is not limited to this.
9. Abdominal/tracheal esophagus or gastrointestinal perforation occurred within 6 months before random assignment.
10. Clinical signs of gastrointestinal obstruction may require routine injection of water, total intravenous nutrition or tube feeding.
11. Extraintestinal gas that cannot be explained by puncture or recent surgery.
12. Severe non-healing wounds, active ulcers, or untreated fractures.
13. Obtain 1.0 g protein in proteinuria through urine test paper or 24-hour urine collection.
All patients whose base-period urine test paper analyzes the protein as 2+ must receive a 24-hour urine collection, and the protein within 24 hours must be 1 g.
14. Known to be allergic to any component of bevacizumab.
15. The radiography clearly shows that the tumor infiltrates the large blood vessels in the thoracic cavity
16. Radiography clearly shows cavitation of lung lesions
Exclusions related to chemotherapy
1. Known to have had severe allergic reactions to platinum-containing compounds or mannitol.
2. Known to be allergic to any component of paclitaxel.
3. According to the definition of the National Cancer Institute's Common Adverse Events Evaluation Criteria (NCI CTCAE) version 4.0, peripheral neuropathy of grade 2 (paclitaxel) occurred
4. Known to have had severe allergic reactions to products containing Cremophor® EL (for example: Cyclosporin injection concentrate and teniposide injection concentrate).
1. Women who are pregnant, breastfeeding, or intend to become pregnant during the trial period.
2. Had severe allergies, systemic allergies or other allergic reactions to chimeric/human-derived antibodies or fusion proteins.
3. Known to be allergic or allergic to the biopharmaceuticals produced by Chinese hamster ovary cells or any ingredients in the atezolizumab formula.
4. Have had autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome related vascular embolism, Wegener's granulomatosis (Wegener's granulomatosis), Sjogren's syndrome (Sjö gren's syndrome), Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis.
Patients with autoimmune hypothyroidism and receiving stable doses of thyroxine supplementation are eligible for this trial.
Patients with well-controlled type 1 diabetes who receive insulin at a stable dose are deemed eligible for this trial.
Patients with leukoplakia who only suffer from eczema, psoriasis, chronic lichen simplex, or only skin disease manifestations (for example, patients with psoriatic arthritis will be excluded) are considered eligible, provided that the following conditions are met:
The rash coverage must be less than 10% of the body surface area (BSA)
The disease is well controlled at the base stage, and only inefficient topical steroids are used
Existing conditions have no acute attacks in the past 12 months (no PUVA therapy [psoralen plus ultraviolet radiation], methotrexate, retinoids, biological agents, oral calcineurin; inhibitors, highly effective Or oral steroids)
5. With a history of spontaneous pulmonary fibrosis, organic pneumonia (bronchiolitis obliterans), drug-induced pneumonia, spontaneous pneumonia, or evidence of acute pneumonia found on a chest computer tomography during screening.
A history of radiation pneumonitis (fibrosis) at the radiotherapy site is permissible.
6. The human immunodeficiency virus (HIV) test result is positive.
All patients will be tested for HIV before being included in the trial; patients with positive HIV test results will not be able to participate in the trial.
7. Patients with acute or chronic hepatitis B and the hepatitis B surface antigen [HBsAg] test result is positive at the time of screening, or patients with hepatitis C.
Patients who have been infected with hepatitis B virus (HBV) or have remission of HBV infection (defined as hepatitis B core antibody [HBcAb] positive and hepatitis B surface antigen [HBsAg] negative) must be HBV DNA negative before they can be regarded as Qualified.
Hepatitis C virus (HCV) antibody-positive patients will be considered eligible only when the polymerized酶 chain reaction (PCR) test shows that hepatitis C virus ribonucleic acid is negative.
8. Active tuberculosis.
9. Serious infections occurred within 4 weeks before random assignment, including but not limited to hospitalization due to infection, bacteremia, or severe pneumonia complications.
10. Have received therapeutic oral or intravenous antibiotics within 2 weeks before random assignment.
Patients who have received prophylactic antibiotics (for example, to prevent urinary tract infections or prevent acute onset of chronic obstructive pulmonary disease) are considered eligible.
11. Major cardiovascular diseases, such as heart disease or cardiovascular accident (level 2 or above) as defined by the New York Heart Association, myocardial infarction, unstable arrhythmia, or unstable angina in the 3 months before random assignment .
Patients who are known to have coronary artery disease, congestive heart failure (but do not meet the above conditions), or left ventricular ejection fraction 50%, must stably receive the best course of treatment identified by the treating physician, and referral should be made when circumstances permit Cardiologist.
12. Randomly assign patients who have undergone major surgical procedures other than diagnosis within the previous 28 days, or are expected to undergo major surgery during the trial period
13. Have received allogeneic bone marrow transplantation or solid organ transplantation.
14. Vaccine live attenuated vaccine within 4 weeks before random assignment, or expect to be vaccinated with live attenuated vaccine during the trial period.
15. The existence of any other diseases, abnormal metabolic function, physical examination findings or clinical laboratory findings can reasonably suspect a certain disease or medical condition, which may make it impossible to use the test drug or may affect the interpretation of the test results, Or increase the patient’s risk of drug complications
16. The patient’s disease or condition will affect his or her ability to understand, follow, and/or follow the test procedures
Drug-related exclusions
1. Receive any approved anti-cancer therapy, including hormonal therapy, within 3 weeks before starting the trial treatment, except for the following conditions:
TKIs (tyrosine inhibitors) approved for the treatment of non-small cell lung cancer have been discontinued for more than 7 days before random assignment. Baseline scans must be performed after stopping the previous TKIs (tyrosine stimulants酶 inhibitors).
2. Receiving other experimental drug treatments with the intent of treatment within 28 days before random assignment.
3. Previously received CD137 agonist or immune checkpoint blocking therapy, anti-PD-1 and anti-PD-L1 therapeutic antibodies.
Patients who have previously received anti-CTLA-4 therapy can be included, provided they meet the following requirements:
It has been at least 6 weeks since receiving the last dose of anti-CTLA-4 before random assignment.
After receiving anti-CTLA-4, no severe immune indirect adverse effects (NCI CTCAE level 3 or 4)
4. Have received systemic immunostimulants (including but not limited to interferon, interleukin-2) within 4 weeks before random assignment or within the five half-life period of the drug (whichever is longer).
It is permissible to have received cancer vaccine before.
5. Received systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents [anti-TNF] within 2 weeks before random assignment ])treatment.
Patients who have received acute, low-dose (oral cortisol [prednisone] 10 mg or equivalent drugs), systemic immunosuppressive drugs, can participate in the trial.
Use of corticosteroids for chronic obstructive pulmonary disease (oral cortisol [prednisone] 10 mg or equivalent), use of mineral cortisol (eg fludrocortisone) for postural hypotension, and use of low doses for lack of adrenal cortex function Corticosteroid supplements are permissible.
Exclusions related to Bevacizumab
1. Poorly controlled hypertension (defined as systolic blood pressure 150 mmHg and/or diastolic blood pressure 100 mmHg)
It is permissible to use antihypertensive therapy to achieve these parameters.
2. With a history of hypertensive crisis or hypertensive encephalopathy
3. Experienced major vascular disease in the 6 months prior to random assignment (for example: aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis).
4. Haemorrhage occurred within 1 month before random assignment ( 2.5 mL of blood each time)
5. Evidence of hemorrhagic constitution or coagulopathy (not receiving anticoagulant treatment).
6. Currently or recently (within 10 days before random assignment) aspirin (325 mg per day), or dipyramidole, ticlopidine, clopidogrel or cilostazol.
7. A full dose of oral or injectable anticoagulant or thrombolytic agent is being used for treatment, but it has not stabilized within 2 weeks before randomization.
As long as the INR and aPTT are within the treatment limits (according to the medical standards of the receiving institution), and the patient is using the anticoagulant at a stable dose for at least 2 weeks before randomization, the oral or injection anticoagulant will be used according to the full dose It is the condition with permission.
Preventive anticoagulants used to maintain the patency of the venous access device in the 14 days prior to random assignment are permissible, but the result of the drug activity is INR 1.5 times the upper limit of normal and aPTT is within the normal range.
The use of preventive low molecular weight heparin (for example: enoxaparin, 40 mg per day) is permissible.
8. Have received a thick needle biopsy or other minor surgery within 7 days before receiving the first dose of bevacizumab, but the placement of the vascular access device is not limited to this.
9. Abdominal/tracheal esophagus or gastrointestinal perforation occurred within 6 months before random assignment.
10. Clinical signs of gastrointestinal obstruction may require routine injection of water, total intravenous nutrition or tube feeding.
11. Extraintestinal gas that cannot be explained by puncture or recent surgery.
12. Severe non-healing wounds, active ulcers, or untreated fractures.
13. Obtain 1.0 g protein in proteinuria through urine test paper or 24-hour urine collection.
All patients whose base-period urine test paper analyzes the protein as 2+ must receive a 24-hour urine collection, and the protein within 24 hours must be 1 g.
14. Known to be allergic to any component of bevacizumab.
15. The radiography clearly shows that the tumor infiltrates the large blood vessels in the thoracic cavity
16. Radiography clearly shows cavitation of lung lesions
Exclusions related to chemotherapy
1. Known to have had severe allergic reactions to platinum-containing compounds or mannitol.
2. Known to be allergic to any component of paclitaxel.
3. According to the definition of the National Cancer Institute's Common Adverse Events Evaluation Criteria (NCI CTCAE) version 4.0, peripheral neuropathy of grade 2 (paclitaxel) occurred
4. Known to have had severe allergic reactions to products containing Cremophor® EL (for example: Cyclosporin injection concentrate and teniposide injection concentrate).
The Estimated Number of Participants
-
Taiwan
90 participants
-
Global
1200 participants
