Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer (OWBLM)
|
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04425681 |
|
Recruitment Status :
Recruiting
First Posted : June 11, 2020
Last Update Posted : June 11, 2020
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC) associated with poor prognosis and rapid deterioration of performance status. The incidence of LM is increasing, reaching 3.8% in molecularly unselected NSCLC patients, being more frequent in adenocarcinoma subtype and up to 9% in epidermal growth factor receptor mutation (EGFRm) lung cancer patients, one-third of patients have concomitant brain metastasis . This increased incidence may in part be conducive to the increased survival of patients with EGFRm advanced NSCLC since the introduction of EGFR-tyrosine kinase inhibitions (TKIs).Currently, no standard therapeutic regimen for LM has been established because of its rarity and heterogeneity[11], and no approved therapies exists to specifically target LM in patients with EGFRm NSCLC. TKIs therapy is the first-line treatment of patients with EGFRm of NSCLC. The leptomeningeal space is a sanctuary site for tumour cells and therapeutic agents due to the presence of an active blood-brain barrier (BBB), so CSF concentration is an important factor affecting treatment of LM by TKIs. Standard-dose first- and second-generation EGFR-TKIs have good systemic efficacy but sub-optimal CNS penetration, as evidenced by preclinical studies of brain distribution and clinical reports of CSF penetration[15, 16]. Osimertinib is a third-generation EGFR-TKI, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, which has demonstrated efficacy in NSCLC CNS metastasis[17-22]. Preclinical, I/II clinical studies and AURA program (AURA extension, AURA2, AURA17 and AURA3) have shown that Osimertinib has higher brain permeability than the first- and second-generation.
Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), animal studies and autopsy specimens show that VEGF plays an important role in LM. VEGF and EGFR share many overlapping and parallel downstream pathways. The biological rationale shows that inhibiting of EGFR and VEGR signaling pathways could improve the efficacy of antitumor and remove the resistance of EGFR inhibition. Besides, preclinical researches have shown the similar results. Based on these, numbers of clinical trials have confirmed that VEGF inhibitors in combination with EGFR-TKI significantly prolong patients' survival.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Leptomeningeal Metastasis Non-small Cell Lung Cancer EGFR Activating Mutation | Drug: Osimertinib Drug: Bevacizumab | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 20 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase II Study of Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer |
| Actual Study Start Date : | October 1, 2017 |
| Estimated Primary Completion Date : | July 1, 2020 |
| Estimated Study Completion Date : | June 1, 2021 |
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Osimertinib With Bevacizumab group
Osimertinib 80 mg oral daily; and bevacizumab 7.5 mg/kg intravenous every 3 weeks
|
Drug: Osimertinib
Treatment of LM With osimertinb Drug: Bevacizumab Treatment of LM With Bevacizumab |
- LM progression-free survival [ Time Frame: up to 1 year ]Time from LM diagnosis to the first documentation of disease progression or death
- Objective Response Rate [ Time Frame: up to 1 year ]ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)
- LM Overall survival [ Time Frame: Every 6 weeks, up to 2 years ]LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up
- progression-free survival [ Time Frame: Every 6 weeks, up to 2 years ]Proportion of patients progression-free by investigator assessment per RECIST v1.1
- adverse events [ Time Frame: Every 3 weeks, up to 2 years ]Number of patients with adverse events (AEs) as a measure of safety and tolerability
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age in 18-80 years
- Pathologically proven NSCLC
- EGFR mutation , the EGFR status was identified from primary lung tumors using the amplification refractory mutation system (ARMS) or next-generation sequencing (NGS) analysis.
- LM diagnosis was based on the detection of malignant cells in the CSF, the focal or diffuse enhancement of leptomeninges, and nerve roots or the ependymal surface on gadolinium-enhanced MRI .
- No severe abnormal liver and kidney function;
- No other severe chronic diseases;
- Signed informed consent form
Exclusion Criteria:
- Patients with the clinical manifestation of nervous system failure including severe encephalopathy, grade III-IV white matter lesions confirmed by imaging examination, moderate or severe coma, and glasgow coma score less than 9 points;
- Allergic to osimertinib or bevacizumab
- Any of the following: Pregnant women ;Nursing women ;Men or women of childbearing potential who are unwilling to employ adequate contraception
- History of myocardial infarction or other evidence of arterial thrombotic disease (angina), symptomatic congestive heart failure (New York Heart Association ≥ grade 2), unstable angina pectoris, or cardiac arrhythmia; Note: allowed only if patient has no evidence of active disease for at least 6 months prior to randomization;
- History of cerebral vascular accident (CVA) or transient ischemic attack (TIA)≤ 6 months prior to randomization
- History of bleeding diathesis or coagulopathy
- History of hemoptysis da≥ grade 2 (defined as bright red blood of at least 2.5 mL) ≤3 months prior to randomization
- Leukocytes below 2*10^9/L, neutrophils below 1*10^9/L; platelets below 50*10^9/L;
- Had major surgery within 60 days;
- History of arteriovenous thrombosis
- Gastrointestinal perforator in the past 6 months
- Inadequately controlled hypertension (systolic blood pressure of > 150 mmHg or diastolic pressure > 100 mmHg on anti-hypertensive medications); Note: history of hypertensive crisis or hypertensive encephalopathy not allowed
- Grade 4 proteinuria
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): NCT04425681
| Contact: Liu Anwen, Phd | +8613767120022 | awliu666@163.com | |
| Contact: Huang s Shu, MD,PhD | +8607918626884 | xiaoshumenfan@126.com |
| China, Jiangxi | |
| The Second Afiliated Hospital of Nanchang University | Recruiting |
| Nanchang, Jiangxi, China, 330006 | |
| Contact: Anwen Liu, MD +8613767120022 awliu666@163.com | |
| Study Director: | Liu Anwen, Phd | Second Affiliated Hospital of Nanchang University |
| Responsible Party: | Second Affiliated Hospital of Nanchang University |
| ClinicalTrials.gov Identifier: | NCT04425681 |
| Other Study ID Numbers: |
20161BBG70210 |
| First Posted: | June 11, 2020 Key Record Dates |
| Last Update Posted: | June 11, 2020 |
| Last Verified: | June 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
|
leptomeningeal metastasis non small cell lung cancer EGFR Activating Mutation Osimertinib Bevacizumab |
|
Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Meningeal Carcinomatosis Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms Neoplastic Processes Pathologic Processes |
Meningeal Neoplasms Central Nervous System Neoplasms Nervous System Neoplasms Nervous System Diseases Bevacizumab Osimertinib Antineoplastic Agents, Immunological Antineoplastic Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Protein Kinase Inhibitors Enzyme Inhibitors |