Clinical trial NCT04425681: Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer
Official title: Phase II Study of Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Leptomeningeal Metastasis
Non-small Cell Lung Cancer
EGFR Activating Mutation
Keywords: leptomeningeal metastasis
non small cell lung cancer
EGFR Activating Mutation
Osimertinib
Bevacizumab
Lead sponsor: Second Affiliated Hospital of Nanchang University
Sponsor class: OTHER
Collaborators: name: Nanchang University
First posted: 2020-06-11
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: This is a phase II pilot study to evaluate the efficacy and safety of osimertinib with bevacizumab for LM from EGFRm NSCLC patients. ALL patients were treated with Osimertinib 80mg oral daily and bevacizumab 7.5mg/kg intravenous every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent.

Eligibility criteria: 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

Primary outcomes:
measure: LM progression-free survival
timeFrame: up to 1 year
measure: Objective Response Rate
timeFrame: up to 1 year
Secondary outcomes:
measure: LM Overall survival
timeFrame: Every 6 weeks, up to 2 years
measure: progression-free survival
timeFrame: Every 6 weeks, up to 2 years
measure: adverse events
timeFrame: Every 3 weeks, up to 2 years
Other outcomes:
Locations:
city: Nanchang
country: China
facility: The Second Afiliated Hospital of Nanchang University
state: Jiangxi
Study officials:
affiliation: Second Affiliated Hospital of Nanchang University
name: Liu Anwen, Phd
role: STUDY_DIRECTOR
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