First Line Treatment in EGFR Mutation Positive Advanced NSCLC Patients With Central Nervous System (CNS) Metastases

Non-small Cell Lung Cancer Clinical Trial

— BM  

Official title:

A Randomized, Open-label, Controlled, Multi-Center Phase II/III Study to Assess the Efficacy and Safety of AZD3759 vs. a Standard of Care EGFR TKI, as First Line Treatment to EGFR Mutation Positive Advanced NSCLC With CNS Metastases

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03653546
• Other study ID #: AZD3759-003
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: October 29, 2018
• Est. completion date: July 12, 2022

Study information

• Verified date: November 2022
• Source: Alpha Biopharma (Jiangsu) Co., Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The first-line treatment with single agent AZD3759 results in superior Progression Free Survival (PFS) compared to Standard of Care (SoC) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI), in patients with advanced EGFR mutation positive non-small cell lung cancer (NSCLC) with Central Nervous System (CNS) metastasis

Description:

This is a Phase II/III randomized, open-label, multicenter study to compare the efficacy and safety of first line single-agent AZD3759 vs. Erlotinib or Gefitinib treatment in patients with advanced EGFR mutation positive NSCLC with CNS metastases.

Eligible patients with documented EGFR mutation+ (L858R and/or Exon 19Del) TKI-naïve advanced NSCLC and documented intracranial disease will be enrolled.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 492
• Est. completion date: July 12, 2022
• Est. primary completion date: July 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Properly completed patient informed consent

2. Male or female aged at least 18 years

3. Histologically or cytologically confirmed diagnosis of NSCLC with activating EGFR mutations including L858R and/or Exon19Del. EGFR mutation status will be determined by local or central laboratory testing on tumour tissue or plasma utilizing a validated methodology which has been approved by the regulatory authority.

4. No prior treatment with chemotherapy, EGFR-TKIs, or biological therapies that are considered first line treatment for advanced NSCLC.

5. All patients must have a documented diagnosis of advanced (Stage IV) NSCLC with Magnetic Resonance Imaging (MRI) documented CNS metastases that include brain metastases (BM). BM + patients with co- existent leptomeningeal involvement are eligible for the study.

6. Eligible patients are not candidates for definitive surgical resection or radiation of all lesions in the opinion of the treating physician.

7. All patients must be stable without any systemic (oral or parenteral) corticosteroid or anticonvulsant therapy for at least 2 weeks prior to study treatment. Inhaled non-absorbable and topical corticosteroid use are permitted as indicated.

8. Patients may have prior placement of a properly functioning CNS shunt or Ommaya reservoir.

9. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks.

10. Women of child-bearing potential and male subjects shall agree to take medically acceptable contraception measures while on study treatment and for 3 months following completion of study treatment. All women of child-bearing potential must have a negative blood pregnancy test at screening.

11. (a) For Patients with measurable CNS lesions must have AT LEAST ONE site of CNS lesion, which was not previously irradiated, that can be accurately measured at baseline as = 10 mm in the longest diameter by MRI and which is suitable for accurate repeated measurements. Measurable extracranial disease is not required. (b) For Patients with non-measurable CNS lesions must have AT LEAST ONE extracranial lesion, which has not been previously irradiated, within the screening period that can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must have short axis = 15 mm) by CT/MRI and are suitable for accurate repeated measurement.

Related Conditions & MeSH terms

• Brain Metastases
• Brain Neoplasms
• EGFR Gene Mutation
• Neoplasm Metastasis
• Non-small Cell Lung Cancer

Intervention

Drug:
• AZD3759
AZD3759 200mg PO BID.
• Erlotinib
SoC EGFRTKI Erlotinib 150 mg PO Q.D
• Gefitinib
SoC EGFRTKI Gefitinib 250 mg PO Q.D

Locations

Country	Name	City	State
China	China site	Beijing
China	China site	Beijing
China	China site	Beijing
China	China site	Beijing
China	China site	Changchun	Jilin
China	China site	Changchun	Jilin
China	China site	Changsha	Hunan
China	China site	Chengdu	Sichuan
China	China site	Chongqing
China	China site	Chongqing
China	China site	Chongqing
China	China site	Fuzhou	Fujian
China	China site	Guangzhou	Guangdong
China	China site	Guangzhou	Guangdong
China	China site	Haerbin	Heilongjiang
China	China site	Hangzhou	Zhejiang
China	China site	Hangzhou	Zhejiang
China	China site	Hangzhou	Zhejiang
China	China site	Hefei	Anhui
China	China site 0123	Jinan	Shandong
China	China site	Kunming	Yunnan
China	China site	Linyi	Shandong
China	China site	Nanjing	Jiangsu
China	China site	Nanjing	Jiangsu
China	China site	Shanghai
China	China site	Shanghai
China	China site	Suzhou	Jiangsu
China	China site	Tianjin
China	China site	Weifang	Shandong
China	China site	Wuhan	Hubei
China	China site	Wuhan	Hubei
China	China site	Wuhan	Hubei
China	China site	Wuxi	Jiangsu
China	China site	Xi'an	Shaanxi
China	China site	Xiamen	Fujian
China	China site	Xuzhou	Jiangsu
China	China site	Yangzhou	Jiangsu
China	China site	Yantai	Shandong
China	China site	Yichang	Hubei
China	China site	Zhengzhou	Henan
China	China site	Zhengzhou	Henan
Korea, Republic of	Korea Site	Chungbuk
Korea, Republic of	Korea site	Daegu
Korea, Republic of	Korea site	Gyeonggi-do
Korea, Republic of	Korea site	Gyeongsang
Korea, Republic of	Korea site	Incheon
Korea, Republic of	Korea Site	Seoul
Korea, Republic of	Korea site	Seoul
Korea, Republic of	Korea Site	Seoul
Korea, Republic of	Korea site	Seoul
Korea, Republic of	Korea site	Seoul
Korea, Republic of	Korea site	Suwon
Korea, Republic of	Korea site	Ulsan
Singapore	Singapore site	Singapore
Taiwan	Taiwan site	Taichung
Taiwan	Taiwan site	Tainan
Taiwan	Taiwan site	Taipei
Taiwan	Taiwan site	Taoyuan

Sponsors (1)

Lead Sponsor	Collaborator
Alpha Biopharma (Jiangsu) Co., Ltd.

Countries where clinical trial is conducted

China,  Korea, Republic of,  Singapore,  Taiwan, 

References & Publications (4)

Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. — View Citation

Barajas RF Jr, Cha S. Imaging diagnosis of brain metastasis. Prog Neurol Surg. 2012;25:55-73. doi: 10.1159/000331174. Epub 2012 Jan 6. Review. — View Citation

Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007 Mar 15;13(6):1663-74. Review. — View Citation

Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008 Jan 1;14(1):162-8. doi: 10.1158/1078-0432.CCR-07-1468. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pop-PK analysis	Population pharmacokinetic analysis	48 months
Other	Exposure-Response analysis	explore the correlation in exposure and efficacy, exposure and safety in the Study	48 months
Primary	PFS assessed by Blinded Independent Central Radiological	To assess if first line treatment with AZD3759 results in significant PFS efficacy compared to Gefitinib or Erlotinib as determined by Blinded Independent Central Radiological (BICR) review using RECIST 1.1.	48 months
Secondary	PFS assess by investigator	Investigator assessment of PFS using RECIST 1.1	48 months
Secondary	Intracranial PFS (iPFS) assessed by investigator	Intracranial PFS (iPFS) assessed by investigator using RECIST 1.1	48 months
Secondary	Intracranial PFS (iPFS) assessed by BICR	Intracranial PFS (iPFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1	48 months
Secondary	Extracranial PFS (ePFS) assessed by investigator	Extracranial PFS (ePFS) assessed by investigator using RECIST 1.1	48 months
Secondary	Extracranial PFS (ePFS) assessed by BICR	Extracranial PFS (ePFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1	48 months
Secondary	Objective Response Rate (ORR) assessed by investigator using RECIST 1.1	Objective Response Rate (ORR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1	48 months
Secondary	Disease Control Rate (DCR) assessed by investigator using RECIST 1.1	Disease Control Rate (DCR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1	48 months
Secondary	Duration of Response (DoR) assessed by investigator using RECIST 1.1	Duration of Response (DoR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1	48 months
Secondary	Overall ORR assessed by investigator using RECIST 1.1	Overall ORR assessed by investigator using RECIST 1.1	48 months
Secondary	Overall DCR assessed by investigator using RECIST 1.1	Overall DCR assessed by investigator using RECIST 1.1	48 months
Secondary	Overall DoR assessed by investigator using RECIST 1.1	Overall DoR assessed by investigator using RECIST 1.1	48 months
Secondary	ORR for Intracranial lesions assessed by investigator using RANO-BM	ORR for Intracranial lesions assessed by investigator using RANO-BM	48 months
Secondary	DCR for Intracranial lesions assessed by investigator using RANO-BM	DCR for Intracranial lesions assessed by investigator using RANO-BM	48 months
Secondary	DoR for Intracranial lesions assessed by investigator using RANO-BM	DoR for Intracranial lesions assessed by investigator using RANO-BM	48 months
Secondary	Overall Survival	Overall Survival	48 months
Secondary	Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).	The 30-items questionnaire measures cancer patients' functioning and symptoms. The scale range of EORTC QLQ-C30 is 30-126. Lower values represent a better outcome.	48 months
Secondary	Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire BN20 (EORTC QLQ-BN20).	The 20-items questionnaire was used among brain cancer patients. The scale range of EORTC BN20 is 20-80. Lower values represent a better outcome.	48 months
Secondary	Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)	Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)	48 months
Secondary	Neurological function improvement rate assessed by RANO-BM criteria	Neurological function improvement rate assessed by RANO-BM criteria	48 months
Secondary	Number of participants with treatment-related Adverse Events as assessed by CTCAE v5.0	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	48 months
Secondary	Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0	Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0	48 months
Secondary	Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0	Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0	48 months
Secondary	Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0	Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0	48 months
Secondary	Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0	Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0	48 months
Secondary	Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.	Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.	48 months
Secondary	Systolic and Diastolic Blood Pressure assessed during the study period.	Systolic and Diastolic Blood Pressure assessed during the study period.	48 months
Secondary	Pulse rate assessed during the study period.	Pulse rate to assessed during the study period.	48 months
Secondary	Body temperature assessed during the study period.	Body temperature assessed during the study period.	48 months
Secondary	PFS assess by BICR	Blinded Independent Central Radiological (BICR) assessment of PFS using modified RECIST 1.1.	48 months