Clinical Trials List
Protocol NumberML29869
NCT Number(ClinicalTrials.gov Identfier)NCT02655536
2015-12-10 - 2019-12-31
Phase II
Recruiting3
ICD-9162.9
Malignant neoplasm of bronchus and lung, unspecified
A PHASE II, OPEN LABEL, MULTICENTER STUDY OF BEVACIZUMAB IN COMBINATION WITH ERLOTINIB VERSUS ERLOTINIB ALONE IN PATIENTS WITH EGFR MUTANT NON-SMALL CELL LUNG CANCER WHO HAVE BRAIN METASTASES.
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Trial Applicant
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Sponsor
National Taiwan University Hospital
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Trial scale
Taiwan Multiple Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 蕭慈慧 Division of Thoracic Medicine
- Yuh-Min Chen Division of Thoracic Medicine
- Heng-Sheng Chao Division of Thoracic Medicine
- Chao-Hua Chiu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Jih-Hsiang Lee Division of Hematology & Oncology
- 廖唯昱 Division of General Internal Medicine
- 林宗哲 Division of Hematology & Oncology
- 蔡子修 Division of General Internal Medicine
- CHAO-CHI HO CHAO-CHI HO Division of General Internal Medicine
- 林育麟 Division of Hematology & Oncology
- 許嘉林 Division of General Internal Medicine
- 吳尚俊 Division of General Internal Medicine
- Chong-Jen Yu Division of General Internal Medicine
- 陳冠宇 Division of General Internal Medicine
- 徐偉勛 Division of Hematology & Oncology
- 楊景堯 Division of General Internal Medicine
- JIN-YUAN SHIH Division of General Internal Medicine
- Chia-Chi Lin Division of Hematology & Oncology
- 廖斌志 Division of Hematology & Oncology
- 吳上俊 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Audit
None
Condition/Disease
NON-SMALL CELL LUNG CANCER WHO HAVE BRAIN METASTASES
Objectives
Primary Objective
To compare the systemic progression-free survival (PFS) to bevacizumab plus erlotinib versus erlotinib alone in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) who have asymptomatic brain metastases.
Secondary Objectives
1. To compare the intracranial and extracranial response rate to bevacizumab plus erlotinib versus erlotinib alone
2. To compare the intracranial and extracranial response duration
1. To compare the time-to-central nervous system (CNS) progression
2. To compare the time to extra-CNS progression
3. For patients who have CNS only progression and continue taking investigating compounds, to compare the second progression-free survival (PFS-2) to bevacizumab plus erlotinib versus erlotinib. The PFS-2 is defined as the duration from start the investigational drug to the timing of the second progression of either intracranial progression or extracranial progression, or patient death.
4. To compare the time to neurological symptom progression
5. To compare the overall survival
6. To evaluate the safety of combining erlotinib and bevacizumab
Exploratory Objectives
1. To investigate genetic and/or protein biomarkers in samples which can correlate to clinical benefit of treatment.
2. To investigate circulating tumor DNA which can correlate to clinical benefit of treatment.
3. To investigate pharmacokinetics of erlotinib in the cerebral spinal fluid upon bevacizumab treatment
4. To collect and store deoxyribonucleic acid (DNA) for future exploratory research into genes/genetic variation that may influence response to bevacizumab and erlotinib treatment.
5. To collect and store tumor tissues for future exploratory research into proteins/genes/genetic variation that may influence response to bevacizumab and erlotinib treatment.
6. To collect and store plasma, serum and archival tumor samples or paired biopsies and analyze surplus blood or tissue, if available, for potential future exploratory research into factors that may influence development of cancer and/or response.
Test Drug
(1)Avastin; (2) Erlotinib
Active Ingredient
BEVACIZUMAB
TARCEVA
TARCEVA
Dosage Form
Injection
Tablet
Tablet
Dosage
100mg/4ml
100mg, 150mg
100mg, 150mg
Endpoints
Efficacy Outcome Measures
Systemic Progression-free survival
Key secondary outcome variables:
1. Overall response rate using RECIST 1.1
2. Time-to-central nervous system (CNS) progression
3. Time to extra-CNS progression
4. The PFS-2 in patients who have CNS only progression and continue taking investigating compounds.
5. Time to neurological symptom progression
6. Overall survival
7. Safety: monitoring the frequency, duration, and severity of AEs and SAEs changes in physical
examination, clinical laboratory parameters, vital signs and ECGs.
Exploratory endpoints
1. Genetic and protein biomarkers in blood or tissue samples which can correlate to clinical benefit of treatment.
2. Circulating tumor DNA which can correlate to clinical benefit of treatment.
3. Pharmacokinetics of erlotinib in the cerebral spinal fluid upon bevacizumab treatment
Systemic Progression-free survival
Key secondary outcome variables:
1. Overall response rate using RECIST 1.1
2. Time-to-central nervous system (CNS) progression
3. Time to extra-CNS progression
4. The PFS-2 in patients who have CNS only progression and continue taking investigating compounds.
5. Time to neurological symptom progression
6. Overall survival
7. Safety: monitoring the frequency, duration, and severity of AEs and SAEs changes in physical
examination, clinical laboratory parameters, vital signs and ECGs.
Exploratory endpoints
1. Genetic and protein biomarkers in blood or tissue samples which can correlate to clinical benefit of treatment.
2. Circulating tumor DNA which can correlate to clinical benefit of treatment.
3. Pharmacokinetics of erlotinib in the cerebral spinal fluid upon bevacizumab treatment
Inclution Criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Pathologically confirmed, stage IV (AJCC 7th Edition) non-small cell lung cancer.
2. A tumor harboring an EGFR mutation known to be associated with erlotinib sensitivity (exon 19
deletion and L858R)
3. Documented brain metastases.
4. At least one measure brain lesion and one extracranial lesion
5. No emergent operation or radiotherapy is indicated. Patients who have received operation for brain tumor may be enrolled if they have recovered from the operation and there are measurable brain lesions after operation.
6. No prior exposure to EGFR inhibitors or anti-angiogenesis therapy including bevacizumab.
7. No prior systemic anti-cancer therapy for advanced NSCLC is allowed. Previous adjuvant or neo-adjuvant treatment for non-metastatic disease is permitted if completed ≥ 6 months before the start of study treatment.
8. Written informed consent obtained prior to any screening procedures.
9. ≥20 years of age.
10. Must have discontinued any previous anti-cancer and investigational therapy for at least 28 days, major operation for at least 28 days with full healing of surgical wounds, or radiotherapy for at least 14 days before study treatment administration, and must have recovered to Grade 1 from the adverse effects of such treatment before starting study treatment.
11. Life expectancy ≥ 3 months.
12. ECOG performance status: 0-1.
13. Female patients of child-bearing potential should have a negative pregnancy test.
14. Required baseline laboratory status:
(1) Hemoglobin>9g/dL
(2) Platelet count≥100x109/L
(3) Absolute neutrophil count (ANC)≥1.5x109/L without growth factor support
(4) Total bilirubin1.5x upper limit of normal (ULN)
(5) AST/SGOT and/or ALT/SGPT2.5x ULN
(6) Serum creatinine clearance >50 ml/min, by either Cockcroft-Gault formula or by 24-hour urine collection analysis
15. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
1. Pathologically confirmed, stage IV (AJCC 7th Edition) non-small cell lung cancer.
2. A tumor harboring an EGFR mutation known to be associated with erlotinib sensitivity (exon 19
deletion and L858R)
3. Documented brain metastases.
4. At least one measure brain lesion and one extracranial lesion
5. No emergent operation or radiotherapy is indicated. Patients who have received operation for brain tumor may be enrolled if they have recovered from the operation and there are measurable brain lesions after operation.
6. No prior exposure to EGFR inhibitors or anti-angiogenesis therapy including bevacizumab.
7. No prior systemic anti-cancer therapy for advanced NSCLC is allowed. Previous adjuvant or neo-adjuvant treatment for non-metastatic disease is permitted if completed ≥ 6 months before the start of study treatment.
8. Written informed consent obtained prior to any screening procedures.
9. ≥20 years of age.
10. Must have discontinued any previous anti-cancer and investigational therapy for at least 28 days, major operation for at least 28 days with full healing of surgical wounds, or radiotherapy for at least 14 days before study treatment administration, and must have recovered to Grade 1 from the adverse effects of such treatment before starting study treatment.
11. Life expectancy ≥ 3 months.
12. ECOG performance status: 0-1.
13. Female patients of child-bearing potential should have a negative pregnancy test.
14. Required baseline laboratory status:
(1) Hemoglobin>9g/dL
(2) Platelet count≥100x109/L
(3) Absolute neutrophil count (ANC)≥1.5x109/L without growth factor support
(4) Total bilirubin1.5x upper limit of normal (ULN)
(5) AST/SGOT and/or ALT/SGPT2.5x ULN
(6) Serum creatinine clearance >50 ml/min, by either Cockcroft-Gault formula or by 24-hour urine collection analysis
15. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
Exclusion Criteria
Patients eligible for this study must not meet any of the following criteria
1. Squamous cell carcinoma
2. Unable or unwilling to swallow tablet once daily.
3. allergy to erlotinib and/or bevacizumab
4. Previous treatment of EGFR inhibitors or anti-angiogenesis therapies.
5. History of gross hemoptysis (defined as bright red blood of at least 1/2 teaspoon or 2.5 mL per episode) within 3 months prior to randomization unless definitively treated with surgery or radiation
6. Symptomatic CNS metastases which are neurologically unstable or requiring increasing doses of steroids to control the CNS condition.
7. CNS bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic) within the last 6 months
8. Chronic daily use of aspirin ( 325 mg/day) or other full-dose NSAIDs with anti platelet activity. Treatment with other antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, and/or cilostazol) is permitted.
9. Other baseline laboratory values
Uncontrolled hypercalcemia ( 11.5 mg/dL)
Urinary protein to creatinine ratio 1 (spot urine)
Serum creatinine 2.0 ULN
10. Radiation therapy within 2 weeks prior to the first dose of study drug. Any persistent side effect of prior radiotherapy must be resolved to Grade 1 prior to the first dose of study treatment.
11. Any unresolved toxicity from previous anticancer therapy > Grade 1.
12. Currently receiving any prohibited medications including vitamins supplements, and herbal supplements.
13. Unable to undergo an MRI or contrast CT procedures.
14. Active HBV or HCV infection, HBV carrier can be enrolled if HBV DNA titer is low under antiviral treatment.
15. Known history of HIV seropositivity. HIV testing is not required as part of this study.
16. Undergone a bone marrow or solid organ transplant.
17. Another malignancy diagnosed or treated within 5 years, except carcinoma in situ or skin cancer.
18. Major surgery within 4 weeks prior to initiating study treatment, excluding the placement of vascular access.
19. Cardiac conditions as
(1) Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy).
(2) myocardial infarction
(3) unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible)
(4) Symptomatic heart failure (NYHA grade II-IV)
(5) Clinically significant peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra abdominal abscess
(6) Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy)
20. Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment, pre-existing idiopathic pulmonary fibrosis or any evidence of clinically active interstitial lung disease.
21. Pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5mIU/mL).
22. Women of child-bearing potential, defined as all women physically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 6 months after stopping study drug. Highly effective contraception methods include:
(1) Male or female sterilization or
(2) Combination of any two of the following:
a. Use oral, injected or implanted hormonal methods of contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository).
23. Women are considered post-menopausal and not of child baring potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
24. Sexually active males must use a condom during intercourse while taking the drug and for 6 more months after stopping study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
25. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, unable to swallow medication, social/psychological issues, etc.
1. Squamous cell carcinoma
2. Unable or unwilling to swallow tablet once daily.
3. allergy to erlotinib and/or bevacizumab
4. Previous treatment of EGFR inhibitors or anti-angiogenesis therapies.
5. History of gross hemoptysis (defined as bright red blood of at least 1/2 teaspoon or 2.5 mL per episode) within 3 months prior to randomization unless definitively treated with surgery or radiation
6. Symptomatic CNS metastases which are neurologically unstable or requiring increasing doses of steroids to control the CNS condition.
7. CNS bleeding; history or clinical evidence of CNS stroke (hemorrhagic or thrombotic) within the last 6 months
8. Chronic daily use of aspirin ( 325 mg/day) or other full-dose NSAIDs with anti platelet activity. Treatment with other antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, and/or cilostazol) is permitted.
9. Other baseline laboratory values
Uncontrolled hypercalcemia ( 11.5 mg/dL)
Urinary protein to creatinine ratio 1 (spot urine)
Serum creatinine 2.0 ULN
10. Radiation therapy within 2 weeks prior to the first dose of study drug. Any persistent side effect of prior radiotherapy must be resolved to Grade 1 prior to the first dose of study treatment.
11. Any unresolved toxicity from previous anticancer therapy > Grade 1.
12. Currently receiving any prohibited medications including vitamins supplements, and herbal supplements.
13. Unable to undergo an MRI or contrast CT procedures.
14. Active HBV or HCV infection, HBV carrier can be enrolled if HBV DNA titer is low under antiviral treatment.
15. Known history of HIV seropositivity. HIV testing is not required as part of this study.
16. Undergone a bone marrow or solid organ transplant.
17. Another malignancy diagnosed or treated within 5 years, except carcinoma in situ or skin cancer.
18. Major surgery within 4 weeks prior to initiating study treatment, excluding the placement of vascular access.
19. Cardiac conditions as
(1) Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy).
(2) myocardial infarction
(3) unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible)
(4) Symptomatic heart failure (NYHA grade II-IV)
(5) Clinically significant peripheral vascular disease, abdominal fistula, gastrointestinal perforation, or intra abdominal abscess
(6) Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy)
20. Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment, pre-existing idiopathic pulmonary fibrosis or any evidence of clinically active interstitial lung disease.
21. Pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5mIU/mL).
22. Women of child-bearing potential, defined as all women physically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 6 months after stopping study drug. Highly effective contraception methods include:
(1) Male or female sterilization or
(2) Combination of any two of the following:
a. Use oral, injected or implanted hormonal methods of contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository).
23. Women are considered post-menopausal and not of child baring potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
24. Sexually active males must use a condom during intercourse while taking the drug and for 6 more months after stopping study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
25. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, unable to swallow medication, social/psychological issues, etc.
The Estimated Number of Participants
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Taiwan
109 participants
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Global
109 participants
