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

Non-small Cell Lung Cancer Clinical Trial

— OWONBNSCLCLM  

Official title:

A Randomized Phase II Trial of Osimertinib Alone or in Combination With Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04148898
• Other study ID #: YC2019-S087
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: November 1, 2019
• Est. completion date: July 1, 2021

Study information

• Verified date: October 2019
• Source: Second Affiliated Hospital of Nanchang University
• Contact: Liu Anwen, Phd
• Phone: +8613767120022
• Email: awliu666[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Description:

This is a randomized phase II clinical trial. The objective of the study is to assess the efficacy of osimertinib combined with bevacizumab for LM from EGFR- mutant NSCLC. Patients were randomized with equal allocation to 80 mg of oral Osimertinib daily alone or with 7.5 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 80
• Est. completion date: July 1, 2021
• Est. primary completion date: March 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• EGFR Activating Mutation
• Leptomeningeal Metastasis
• Lung Neoplasms
• Meningeal Carcinomatosis
• Neoplasm Metastasis
• Neoplasms, Second Primary
• Non-small Cell Lung Cancer

Intervention

Drug:
• Osimertinib
Treatment of LM With osimertinb
• Bevacizumab
Treatment of LM With osimertinb combined with bevacizumab

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Second Affiliated Hospital of Nanchang University	Nanchang University

References & Publications (10)

Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, Pickup K, Jordan A, Hickey M, Grist M, Box M, Johnström P, Varnäs K, Malmquist J, Thress KS, Jänne 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. Epub 2016 Jul 19. — View Citation

Cai Z, Liu Q. Understanding the Global Cancer Statistics 2018: implications for cancer control. Sci China Life Sci. 2019 Aug 26. doi: 10.1007/s11427-019-9816-1. [Epub ahead of print] — View Citation

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. Review. — View Citation

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. — View Citation

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, Rudà 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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,
Primary	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	LM Overall survival	LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up	Every 3 weeks, up to 5 years,
Secondary	progression-free survival	Proportion of patients progression-free by investigator assessment per RECIST v1.1	Every 6 weeks, up to 2 years,
Secondary	adverse events	Number of patients with adverse events (AEs) as a measure of safety and tolerability	Every 3 weeks, up to 2 years,