Osimertinib With or Without Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis

NCT04148898 | Unknown Phase 2 DMC

• 1 other identifier: YC2019-S087
• Study Type: interventional
• Target: 80
• Locations: 0 countries
• Sites: N/A

Brief Summary

Leptomeningeal metastasis (LM) is a devastating and terminal complication of advanced non-small-cell lung cancer (NSCLC), especially in patients harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib is an oral,third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations .AURA I/II study and other preclinical study suggested that Osimertinib exhibited a better blood-brain barrier(BBB) penetration than the other EGFR-TKIs (gefitinib, erlotinib, or afatinib).The BLOOM 、AURA and FLURA study demonstrated that osimertinib showed encouraging activity and manageable tolerability in pretreated EGFR-mutant NSCLC patients with LM. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF). Animal study and autopsy specimens showed that VEGF is an essential factor in LM. Recently study showed EGFR-TKIs plus bevacizumab prolonged PFS and OS in patients with EGFR-mutant NSCLC and multiple brain mteastasis when compared with EGFR-TKIs alone. Howerver osimertinib combined with bevacizumab could benefit patients with LM from EGFR- mutant NSCLC remains undetermined. Therefore, the purpose of the study is to evaluate the safety and efficacy of osimertinib combined with bevacizumab for EGFR- mutant non-small cell lung cancer with leptomeningeal metastasis

Conditions

Leptomeningeal Metastasis; Non-small Cell Lung Cancer; EGFR Activating Mutation

Keywords

leptomeningeal metastasis; non small cell lung cancer; EGFR Activating Mutation; Osimertinib; Bevacizumab

Outcome Measures

Primary Outcomes (2)

• Intracranial progression-free

  iPFS (Time from LM diagnosis to the first documentation of intracranial lesion progression or death with documented intracranial pro- gression,)

  Every 6 weeks, up to 2 years,

• Objective Response Rate

  ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)

  Every 6 weeks, up to 2 years

Secondary Outcomes (3)

• LM Overall survival

  Every 3 weeks, up to 5 years,

• progression-free survival

  Every 6 weeks, up to 2 years,

• adverse events

  Every 3 weeks, up to 2 years,

Study Arms (2)

osimertinb group

EXPERIMENTAL

Osimertinib 80 mg oral daily

Drug: Osimertinib

osimertinb combined with bevacizumab group

EXPERIMENTAL

Osimertinib 80 mg oral daily; .bevacizumab 7.5 mg/kg intravenous every 3 weeks

Drug: Osimertinib; Drug: Bevacizumab

Interventions

Osimertinib DRUG

Treatment of LM With osimertinb

Also known as: AZD9291

osimertinb combined with bevacizumab group; osimertinb group

Bevacizumab DRUG

Treatment of LM With osimertinb combined with bevacizumab

Also known as: Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb

osimertinb combined with bevacizumab group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Second Affiliated Hospital of Nanchang University: lead
• Nanchang University: collaborator

Related Publications (10)

• Cai Z, Liu Q. Understanding the Global Cancer Statistics 2018: implications for cancer control. Sci China Life Sci. 2021 Jun;64(6):1017-1020. doi: 10.1007/s11427-019-9816-1. Epub 2019 Aug 26. No abstract available.

  PMID: 31463738 BACKGROUND

• Liao BC, Lee JH, Lin CC, Chen YF, Chang CH, Ho CC, Shih JY, Yu CJ, Yang JC. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-Small-Cell Lung Cancer Patients with Leptomeningeal Carcinomatosis. J Thorac Oncol. 2015 Dec;10(12):1754-61. doi: 10.1097/JTO.0000000000000669.

  PMID: 26334749 BACKGROUND

• Zhou Q, Song Y, Zhang X, Chen GY, Zhong DS, Yu Z, Yu P, Zhang YP, Chen JH, Hu Y, Feng GS, Song X, Shi Q, Yang LL, Zhang PH, Wu YL. A multicenter survey of first-line treatment patterns and gene aberration test status of patients with unresectable Stage IIIB/IV nonsquamous non-small cell lung cancer in China (CTONG 1506). BMC Cancer. 2017 Jul 3;17(1):462. doi: 10.1186/s12885-017-3451-x.

  PMID: 28673332 BACKGROUND

• Wu YL, Zhao Q, Deng L, Zhang Y, Zhou XJ, Li YY, Yu M, Zhou L, Zou BW, Lu Y, Liu YM. Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer. Lung Cancer. 2019 Jan;127:1-5. doi: 10.1016/j.lungcan.2018.11.022. Epub 2018 Nov 20.

  PMID: 30642536 BACKGROUND

• Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer. Lancet Oncol. 2018 Jan;19(1):e43-e55. doi: 10.1016/S1470-2045(17)30689-7.

  PMID: 29304362 BACKGROUND

• Reijneveld JC, Taphoorn MJ, Kerckhaert OA, Drixler TA, Boogerd W, Voest EE. Angiostatin prolongs the survival of mice with leptomeningeal metastases. Eur J Clin Invest. 2003 Jan;33(1):76-81. doi: 10.1046/j.1365-2362.2003.01056.x.

  PMID: 12492456 BACKGROUND

• Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, Pickup K, Jordan A, Hickey M, Grist M, Box M, Johnstrom P, Varnas K, Malmquist J, Thress KS, Janne PA, Cross D. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016 Oct 15;22(20):5130-5140. doi: 10.1158/1078-0432.CCR-16-0399. Epub 2016 Jul 19.

  PMID: 27435396 BACKGROUND

• Jiang T, Chu Q, Wang H, Zhou F, Gao G, Chen X, Li X, Zhao C, Xu Q, Li W, Wu F, Xiong A, Zhao J, Xu Y, Su C, Ren S, Zhou C, Hirsch FR. EGFR-TKIs plus local therapy demonstrated survival benefit than EGFR-TKIs alone in EGFR-mutant NSCLC patients with oligometastatic or oligoprogressive liver metastases. Int J Cancer. 2019 May 15;144(10):2605-2612. doi: 10.1002/ijc.31962. Epub 2018 Dec 8.

  PMID: 30387880 BACKGROUND

• Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. doi: 10.1200/JCO.2018.77.9363. Epub 2018 Jul 30.

  PMID: 30059262 BACKGROUND

• Le Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W, Wesseling P, Ruda R, Preusser M; EANO Executive Board and ESMO Guidelines Committee. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol. 2017 Jul 1;28(suppl_4):iv84-iv99. doi: 10.1093/annonc/mdx221. No abstract available.

  PMID: 28881917 BACKGROUND

MeSH Terms

Conditions

Meningeal Carcinomatosis; Carcinoma, Non-Small-Cell Lung

Interventions

osimertinib; Bevacizumab

Condition Hierarchy (Ancestors)

Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Liu Anwen, Phd

  Second Affiliated Hospital of Nanchang University

  STUDY DIRECTOR

Central Study Contacts

Liu Anwen, Phd

CONTACT

+8613767120022; awliu666@163.com

Cai Jing, Phd

CONTACT

+8615270905381; cjdl879@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: single
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Crossover Assignment

Study Record Dates

• First Submitted: October 3, 2019
• First Posted: November 4, 2019
• Study Start: November 1, 2019
• Primary Completion: March 1, 2021
• Study Completion: July 1, 2021
• Last Updated: November 4, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share