Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer

Non-small Cell Lung Cancer Clinical Trial

— OWBLM  

Official title:

Phase II Study of Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04425681
• Other study ID #: 20161BBG70210
• Status: Recruiting
• Phase: Phase 2
• Start date: October 1, 2017
• Est. completion date: June 1, 2021

Study information

• Verified date: June 2020
• 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 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: June 1, 2021
• Est. primary completion date: July 1, 2020
• 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 Bevacizumab

Locations

Country	Name	City	State
China	The Second Afiliated Hospital of Nanchang University	Nanchang	Jiangxi

Sponsors (2)

Lead Sponsor	Collaborator
Second Affiliated Hospital of Nanchang University	Nanchang University

Country where clinical trial is conducted

China, 

References & Publications (14)

Akamatsu H, Teraoka S, Morita S, Katakami N, Tachihara M, Daga H, Yamamoto N, Nakagawa K. Phase I/II Study of Osimertinib With Bevacizumab in EGFR-mutated, T790M-positive Patients With Progressed EGFR-TKIs: West Japan Oncology Group 8715L (WJOG8715L). Cli — View Citation

Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, — View Citation

De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, Aldinucci D, Pinto A, Normanno N. The role of the EGFR signaling in tumor microenvironment. J Cell Physiol. 2008 Mar;214(3):559-67. Review. — View Citation

Flippot R, Biondani P, Auclin E, Xiao D, Hendriks L, Le Rhun E, Leduc C, Beau-Faller M, Gervais R, Remon J, Adam J, Planchard D, Lavaud P, Naltet C, Caramella C, Le Pechoux C, Lacroix L, Gazzah A, Mezquita L, Besse B. Activity of EGFR Tyrosine Kinase Inhi — View Citation

Gregorc V, Lazzari C, Karachaliou N, Rosell R, Santarpia M. Osimertinib in untreated epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer. Transl Lung Cancer Res. 2018 Apr;7(Suppl 2):S165-S170. doi: 10.21037/tlcr.2018.03.19. — View Citation

Hochmair M. Medical Treatment Options for Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Suffering from Brain Metastases and/or Leptomeningeal Disease. Target Oncol. 2018 Jun;13(3):269-285. doi: 10.1007/s11523- — View Citation

Lv Y, Mu N, Ma C, Jiang R, Wu Q, Li J, Wang B, Sun L. Detection value of tumor cells in cerebrospinal fluid in the diagnosis of meningeal metastasis from lung cancer by immuno-FISH technology. Oncol Lett. 2016 Dec;12(6):5080-5084. doi: 10.3892/ol.2016.531 — View Citation

Masuda C, Yanagisawa M, Yorozu K, Kurasawa M, Furugaki K, Ishikura N, Iwai T, Sugimoto M, Yamamoto K. Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model. Int J Oncol. 2017 Aug;51(2):425-434. doi: 10.389 — View Citation

Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; F — View Citation

Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramali — View Citation

Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res. 2007 Mar;5(3):203-20. Review. — View Citation

Taillibert S, Chamberlain MC. Leptomeningeal metastasis. Handb Clin Neurol. 2018;149:169-204. doi: 10.1016/B978-0-12-811161-1.00013-X. Review. — View Citation

Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, Horita N, Segawa Y, Hamada N, Takata I, Yamane H, Kamei H, Kiura K, Tanimoto M. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung — 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 — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	LM progression-free survival	Time from LM diagnosis to the first documentation of disease progression or death	up to 1 year
Primary	Objective Response Rate	ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)	up to 1 year
Secondary	LM Overall survival	LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up	Every 6 weeks, up to 2 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