Phase Ⅲ Trial of WBRT Versus Erlotinib Concurrent Whole-brain Radiation Therapy as first-line Treatment for Patients With Multiple Brain Metastases From Non-small-cell Lung Cancer(ENTER): a Multicentre, Open-label, Randomised Study

1. Verify the effect of Erlotinib concurrent whole-brain radiation therapy as first-line treatment for patients with multiple brain metastases from non-small-cell lung cancer to compare with WBRT alone.
2. Verify pre-built EGFR mutation prediction model for NSCLC brain metastases

Study Overview

• Status: Completed
• Conditions: Non-small-cell Lung Cancer; Multiple Brain Metastases
• Intervention / Treatment: Drug: Erlotinib; Drug: WBRT

Detailed Description

All patients will be randomized to receive WBRT or Erlotinib concurrent WBRT. Erlotinib concurrent WBRT, patients were given a loading dose of erlotinib 150mg per day for 6 days, after which all patients received erlotinib 150mg per day concurrently with WBRT. Dose reduction was allowed for intolerable adverse effects (grade ≥3) such as rash or diarrhea in 50 mg increments down from 150mg to 100 mg and then to 50 mg if needed. Radiation therapy was delivered in 2.0 Gy fractions once per day 5 days per week to a total dose of 40Gy (20 fractions). Radiation was delivered as opposed lateral 8-MV beams with a Sweden precise linear accelerator.

• Study Type: Interventional
• Enrollment (Actual): 224
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Chongqing
    • Chongqing, Chongqing, China
      • Zhenzhou-Yang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 years of age or older;
2. the pathological diagnosis of non-small cell lung cancer and detection of pulmonary primary ARMs / sequencing EGFR mutation;
3. enhanced MRI showed brain metastases ≥ 2 or NSCLC of brain metastases after resection of residual lesions in ≥ 2 / intracranial metastases in patients with new;
4. if the previous use of EGFR-TKIs, in an WBRT synchronous Erotinib before treatment to disable EGFR-TKIs ≥ 4 weeks;
5. expected survival period over 2 months;
6. KPS score ≥ 70;
7. GPA score 0.5 - 3.5;

8. a week before randomization, bone marrow and liver and kidney function in patients with meet the following criteria:

   1. HB ≥ 100, g/L ≥ 1.5 × 109/L neutrophil and platelet ≥ 100 × 109/L;
   2. total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal;
   3. more than 1.5 times the upper limit of normal serum creatinine or creatinine clearance rate ≥ 60 ml/min, urea N ≤ 200mg/L;
   4. Urine dipstick testing the proteinuria < 1+; if the urine dipstick test value, 1+, is 24 hours total urine protein must < 500mg.
9. compliance research plan and follow-up process, and be able to carry out oral therapy;
10. in women of childbearing age, must be in before starting treatment within 7 day of urine pregnancy test and the result is negative, and not in the lactation period, and reproductive age men and women prior to entry into the study, the research process until 90 days after stopping all agree to use reliable methods of contraception;
11. can understand and consent.

Exclusion Criteria:

1. patients have been treated with radiation to the brain or to erlotinib and its ingredients allergies;
2. mixed with small cell lung cancer patients with components;
3. 5 years before other cancers except NSCLC treatment in patients with the start of the study (except for simple operation resection and there are at least 5 consecutive years disease free survival, has been cured of cervical carcinoma in situ, has cured the base cell cancer and bladder epithelial tumor);
4. before entering the group 4 weeks received any other investigational drugs;
5. judgment according to the researchers, there are serious harm to patient safety or affect the patients completed the study with the disease, and patient compliance with the difference;
6. had any clinical evidence of moderate to severe chronic obstructive pulmonary disease (COPD -COPD a history or risk factors of pulmonary function testing, FEV1/FVC<70%, FEV1<80% estimates, with or without chronic cough, sputum, difficulty breathing), activity of interstitial lung disease (-ILD pulmonary function test FEV1/FVC<70%, FEV1<80% estimates, dispersion carbon monoxide lung volume -DLCO<40%, high resolution CT showed a diffuse interstitial lung disease) disease activity and other researchers decided;
7. on gastrointestinal physiology is not perfect, or absorb the obstacle syndrome, or unable to tolerate oral medication, or active peptic ulcer;
8. any unstable system diseases: including active infection, uncontrolled hypertension, unstable angina pectoris, within the last 3 months of the onset of angina, congestive heart failure, the group in June before the myocardial infarction, need serious mental disorder drug treatment, liver, kidney or metabolic diseases; mental / spiritual diseases such as Alzheimer's disease;
9. without full control of ocular inflammation or eye infections, or any may cause the eye disease situation;
10. known human immunodeficiency virus (HIV) infection;
11. with immunodeficiency disease, or suffer from other acquired, congenital immunodeficiency disease, or a history of organ transplantation;
12. any disease, metabolic disorders, or physical examination or laboratory suspicion or treatment of complications in patients at high risk of drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1. WBRT alone; Selected 224 patients with multiple brain metastases from NSCLC, they will be randomized to WBRT or Erotinib concurrent WBRT. It was enough to compare the efficacy of Erotinib concurrent WBRT vs. WBRT	Drug: WBRT
EXPERIMENTAL: 2. Erlotinib concurrent WBRT; Selected 224 patients with multiple brain metastases from NSCLC, they will be randomized to WBRT or Erotinib concurrent WBRT. It was enough to compare the efficacy of Erotinib concurrent WBRT vs. WBRT	Drug: Erlotinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to neurologic progression	A) assess the local control of brain metastases status (including: the proportion of salvage therapy, the proportion of radiation necrosis lesions) B) evaluation of intracranial metastasis status (at the site of the primary tumor than the emergence of new brain metastases)	13 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	3 years
Quality of Life	3 years
Complete response, Partial response, Stable disease, Progressive disease	19 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The purpose of exploring	Focal EGFR 1 certification pre built NSCLC mutation prediction model of brain metastasis.; Blood sample was collected for patients with Erotinib biomarker research.	3 years

Collaborators and Investigators

• Sponsor: Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Publications and helpful links

General Publications

• Yang Z, Zhang Y, Li R, Yisikandaer A, Ren B, Sun J, Li J, Chen L, Zhao R, Zhang J, Xia X, Liao Z, Carbone DP. Whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases: a multicenter, open-label, randomized, controlled phase III trial. Neuro Oncol. 2021 Jun 1;23(6):967-978. doi: 10.1093/neuonc/noaa281.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (ACTUAL): August 1, 2016
• Study Completion (ACTUAL): August 1, 2016

Study Registration Dates

• First Submitted: June 8, 2013
• First Submitted That Met QC Criteria: June 26, 2013
• First Posted (ESTIMATE): June 27, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): August 25, 2016
• Last Update Submitted That Met QC Criteria: August 24, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Data collection; Informed Consent;; Ethical Principles
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: Yang-1970