Bevacizumab in the Treatment of Malignant Pleural Effusions of Non-squamous Non-small Cell Lung Cancer

Malignant Pleural Effusion Clinical Trial

Official title:

A Prospective, Multicenter, Randomized Controlled Clinical Trial of Bevacizumab in the Treatment of Malignant Pleural Effusions of Non-squamous Non-small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02942043
• Other study ID #: 20160204
• Status: Recruiting
• Phase: Phase 2
• Start date: October 2016
• Est. completion date: October 2019

Study information

• Verified date: November 2018
• Source: Beijing Cancer Hospital
• Contact: Jian Fang
• Phone: +86-010-88196459
• Email: bcht2_mj[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to explore the efficacy and safety of different doses of bevacizumab injection in the treatment of malignant pleural effusion in patients with advanced non-squamous non-small cell lung cancer.

Description:

This study is a prospective, multicenter, randomized, phase II clinical study. 87 patients will be recruited.

Group A (low dose group)

Intrapleural injection of bevacizumab 2.5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard.

Group B (medium dose group)

Intrapleural injection of bevacizumab 5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard.

Group C (high dose group)

Intrapleural injection of bevacizumab 7.5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard.

Main evaluation criteria: pleural effusion objective response rate(ORR) (WHO standard)

Secondary evaluation criteria: pleural fluid time to progression (TTP), overall survival (OS), ORR, QOL scores (Quality of Life Questionnaire-lung cancer) and KPS, and safety (NCI CTCAE V4.03)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 87
• Est. completion date: October 2019
• Est. primary completion date: May 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Voluntarily sign informed consent;

2. Non-squamous non-small cell lung cancer, newly diagnosed or previously treated with systemic chemotherapy and / or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors treatment;

3. B ultrasound, chest X-ray or CT examination to a large number of pleural effusion, with a cytology confirm of malignant pleural effusion;

4. Aged 18-75 years;

5. Eastern Cooperative Oncology Group (ECOG) score = 2;

6. Survival is expected to exceed 8 weeks

Exclusion Criteria:

If any of the following criteria is met, the subject shall be excluded:

1. Squamous cell carcinoma (including adenosquamous carcinoma) and small cell lung cancer (including small cell carcinoma and non-small cell mixed lung cancer);

2. In the past 2 weeks, there have been systematic anti-tumor treatment including chemotherapy (including thoracic chemotherapy), radiotherapy (excluding radiotherapy of metastatic lesions outside the thoracic radiation field), targeted therapy, immunotherapy and biotherapy;

3. The subject had received anti-vascular endothelial growth factor (VEGF) small molecule tyrosine kinase inhibitors or monoclonal antibodies in the past 4 weeks;

4. The subject had participated any clinical trials in the past 4 weeks;

5. The subject had previously received bevacizumab of pleural perfusion therapy;

6. Laboratory results:

• White blood cell count <3 × 109 / L, neutrophil count <1.5 × 109 / L, platelet <75 × 109 / L, or hemoglobin <8g / dL;

• Coagulation abnormalities (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or activated partial thromboplastin time (APTT) > 1.5 ULN), with bleeding tendency or being treated with thrombolysis or anticoagulation;

• Serum total bilirubin =1.5 ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) = 2.5 ULN in the absence of liver metastases; ALT or AST =5 ULN in liver metastases;

• Serum albumin <30g / L;

• Serum creatinine = 1.5 ULN or creatinine clearance <40ml / min;

• Urine routine urinary protein = ++, or 24 hours urine protein = 1.0 g;

7. Hypertension cannot be controlled by drugs;

8. Heart disease with significant clinical symptoms, such as: congestive heart failure, coronary heart disease with symptom, arrhythmia hardly be controlled by drugs, myocardial infarction in 6 months, or heart failure;

9. Imaging (CT or MRI) showed a tumor lesion 5 mm away from the large vessels, or the presence of invasive central vasculature of the central tumor; imaging (CT or MRI) showed significant cavitation or necrosis of the lung tumor; Other diseases that may cause haemoptysis;

10. Imaging (CT or chest radiograph) showed significant pneumothorax, fluid pneumothorax;

11. Bilateral pleural cavity to a large number of effusion or encapsulated pleural effusion;

12. Obvious cough blood in 6 months, or daily hemoptysis amounted to half a teaspoon (2.5ml) or more;

13. Significant bleeding symptoms or with definite bleeding tendency within 12 months before randomization, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, occult blood ++ and above, intracerebral hemorrhage, vasculitis, or with congenital or acquired coagulopathy disorders;

14. Thrombosis, cancer thrombosis (including arteriovenous thrombosis, tumor thrombus, pulmonary embolism, transient ischemic attack, etc.) occurred within 12 months;

15. There are gastrointestinal obstruction, peptic ulcer, Crohn's disease, ulcerative colitis and other gastrointestinal diseases or other diseases may cause gastrointestinal bleeding or perforation;

16. Severe respiratory diseases, or need long-term oxygen, corticosteroid treatment of diseases such as chronic obstructive pulmonary disease, interstitial lung disease and respiratory failure;

17. The toxicity of previous antineoplastic therapies has not yet recovered to below grade 2 or has not fully recovered;

18. Patients with uncontrolled central nervous system metastasis;

19. There are serious uncontrolled systemic diseases, such as nephrotic syndrome, infection, poorly controlled diabetes;

20. Patients with active HIV(human immunodeficiency virus), HBV(hepatitis B virus), or HCV(hepatitis C virus) infection;

21. Patients had undergone surgery (<28 days) or did not heal completely, or had other unhealed wounds before the study;

22. Patients known to be allergic to bevacizumab or any of the components of the drug;

23. Pregnant or lactating female patients, or unwilling to take contraceptive measures of reproductive age patients (including men);

24. There is a serious psychological or mental abnormality, or lack of compliance;

25. The investigator determines other circumstances that may affect the conduct of clinical studies and the determination of findings.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Malignant Pleural Effusion
• Pleural Effusion
• Pleural Effusion, Malignant

Intervention

Drug:
• Bevacizumab
Group A (low dose group) Intrapleural injection of bevacizumab 2.5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard. Group B (medium dose group) Intrapleural injection of bevacizumab 5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard. Group C (high dose group) Intrapleural injection of bevacizumab 7.5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard.

Locations

Country	Name	City	State
China	Beijing Cancer Hospital	Beijing	Beijing

Sponsors (3)

Lead Sponsor	Collaborator
Beijing Cancer Hospital	Peking University First Hospital, Peking University Third Hospital

Country where clinical trial is conducted

China, 

References & Publications (15)

Bae SH, Hwang JY, Kim WJ, Yoon HH, Kim JM, Nam YH, Baek HG, Cho YR, Park SY, Kim JH, Kim SH, Park TH, Lee GN, Rha SH, Kim YD. A case of cardiac amyloidosis with diuretic-refractory pleural effusions treated with bevacizumab. Korean Circ J. 2010 Dec;40(12) — View Citation

Du N, Li X, Li F, Zhao H, Fan Z, Ma J, Fu Y, Kang H. Intrapleural combination therapy with bevacizumab and cisplatin for non-small cell lung cancer-mediated malignant pleural effusion. Oncol Rep. 2013 Jun;29(6):2332-40. doi: 10.3892/or.2013.2349. Epub 2013 Mar 15. — View Citation

El-Shami K, Elsaid A, El-Kerm Y. Open-label safety and efficacy pilot trial of intraperitoneal bevacizumab as palliative treatment in refractory malignant ascites. J Clin Oncol.2007;25(18 suppl):9043

Hama M, Komatsu Y, Hachiya T. [A case of lung cancer showing marked reduction of pleural effusion by bevacizumab in combination with carboplatin and paclitaxel]. Gan To Kagaku Ryoho. 2011 Nov;38(11):1877-9. Japanese. — View Citation

Hamilton CA, Maxwell GL, Chernofsky MR, Bernstein SA, Farley JH, Rose GS. Intraperitoneal bevacizumab for the palliation of malignant ascites in refractory ovarian cancer. Gynecol Oncol. 2008 Dec;111(3):530-2. doi: 10.1016/j.ygyno.2008.04.028. Epub 2008 J — View Citation

Kesterson JP, Mhawech-Fauceglia P, Lele S. The use of bevacizumab in refractory ovarian granulosa-cell carcinoma with symptomatic relief of ascites: a case report. Gynecol Oncol. 2008 Dec;111(3):527-9. doi: 10.1016/j.ygyno.2008.07.015. Epub 2008 Aug 16. — View Citation

Kitamura K, Kubota K, Ando M, Takahashi S, Nishijima N, Sugano T, Toyokawa M, Miwa K, Kosaihira S, Noro R, Minegishi Y, Seike M, Yoshimura A, Gemma A. Bevacizumab plus chemotherapy for advanced non-squamous non-small-cell lung cancer with malignant pleura — View Citation

Masago K, Fujimoto D, Fujita S, Hata A, Kaji R, Ohtsuka K, Okuda C, Takeshita J, Katakami N. Response to bevacizumab combination chemotherapy of malignant pleural effusions associated with non-squamous non-small-cell lung cancer. Mol Clin Oncol. 2015 Mar; — View Citation

Medford AR, Maskell NA. A national survey of oncologist and chest physicians' attitudes towards empirical anti-oestrogen therapy, early pleurodesis and preference of sclerosing agent in malignant breast and ovarian pleural disease. Palliat Med. 2005 Jul;1 — View Citation

Mitsuhiro Fuji, Shin-Ichiro Iwakami1, Hiroaki Ihara. Efficacy and safety of chemotherapy containing bevacizumab in patients with non-small cell lung cancer with malignant pleural effusion. Respirology. 2013;18 (Suppl.4): 87

Numnum TM, Rocconi RP, Whitworth J, Barnes MN. The use of bevacizumab to palliate symptomatic ascites in patients with refractory ovarian carcinoma. Gynecol Oncol. 2006 Sep;102(3):425-8. Epub 2006 Jun 23. — View Citation

Pichelmayer O, Gruenberger B, Zielinski C, Raderer M. Bevacizumab is active in malignant effusion. Ann Oncol. 2006 Dec;17(12):1853. Epub 2006 Jun 21. — View Citation

Pichelmayer O, Zielinski C, Raderer M. Response of a nonmalignant pleural effusion to bevacizumab. N Engl J Med. 2005 Aug 18;353(7):740-1. — View Citation

Seto T, Ushijima S, Yamamoto H, Ito K, Araki J, Inoue Y, Semba H, Ichinose Y; Thoracic Oncology Group. Intrapleural hypotonic cisplatin treatment for malignant pleural effusion in 80 patients with non-small-cell lung cancer: a multi-institutional phase II — View Citation

Tamiya M, Tamiya A, Yamadori T, Nakao K, Asami K, Yasue T, Otsuka T, Shiroyama T, Morishita N, Suzuki H, Okamoto N, Okishio K, Kawaguchi T, Atagi S, Kawase I, Hirashima T. Phase2 study of bevacizumab with carboplatin-paclitaxel for non-small cell lung can — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pleural effusion ORR		1 year
Secondary	Pleural fluid TTP		1 year
Secondary	OS		1 year
Secondary	ORR		1 year
Secondary	QOL scores		2 month
Secondary	Safety (NCI CTCAE V4.03)		2 month