Gefitinib Combined With Chemotherapy or Antiangiogensis in Patients With Bim Deletion or Low EGFR Mutation Abundance

Combination of Gefitinib With Chemotherapy or Anti-angiogenesis as 1st Line Treatment in Advanced NSCLC Patients Detected With Bim Deletion or Low EGFR Activating Mutation Abundance

This is a single arm phase II clinical trial, which aims to evaluate the effectiveness of combination of gefitinib and doublet chemotherapy or antiangiogenesis in advanced non-small cell lung cancer patients with EGFR activating mutation, accompanied with Bim deletion or low activating EGFR mutation abundance.

Study Overview

• Status: Unknown
• Conditions: Non-small-cell Lung Cancer
• Intervention / Treatment: Drug: Gefitinib; Drug: pemetrexed or gemcitabine plus carboplatin,; Drug: bevacizumab

Detailed Description

BIM deletion polymorphism and low EGFR mutation abundance were poor clinical response markers to EGFR-TKIs in NSCLC patients who had EGFR mutations.This is a phase II clinical trial to investigate the efficacy of combination treatment for patients harboring risk factors.

Advanced EGFR mutated NSCLC Patients with Bim deletion or EGFR low mutation abundance were randomizely divided into three treatment groups:

A:Gefitinib 250mg Qd B:Gefitinib 250mg Qd combined with doublet chemotherapy: Pemetrexed (500mg/m²day 1 intravenously) plus carboplatin (AUC=5,day 1,intravenously) every 21 days, Gemcitabine (1000 mg/m² days 1, day8, intravenously) plus carboplatin (AUC=5,day 1,intravenously) every 21 days C:Gefitinib 250mg Qd combined with bevacizumab 7.5mg/kg intravenously per 21 days.

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Caicun Zhou, MD,PhD; Phone Number: 3049 86-21-65115006; Email: caicunzhoudr@163.com
• Study Contact Backup: Name: shengxiang Ren, MD,PhD; Phone Number: 3050 86-21-65115006; Email: harry_ren@126.com

Study Locations

• China
  • Shanghai, China, 200433
    • Department of Oncology, Shanghai pulmonary hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically documented, locally advanced or recurrent (stage IIIb and not amenable to combined modality treatment) or metastatic (stage IV) non-small cell lung cancer, anti-cancer treatment naiive
• EGFR exon 19 deletion or exon 21 L858R.
• Bim deletion by realtime PCR, or low abundance for EGFR mutation, for 19Del less than 4.9%, for L858R less than 9.5%.
• ECOG performance status of ≤ 1.
• Patients must have measurable disease according to the RECIST (version 1.1) criteria.
• Life expectancy of at least 12 weeks
• Written (signed) informed Consent to participate in the study.
• Adequate organ function as defined by the following criteria:

Liver function: SGOT (AST) and SGPT (ALT) ≤ 2.5 X ULN in the absence of liver metastases or up to 5 X ULN in case of liver metastases. Total bilirubin ≤ 1.5ULN.

Bone marrow function: Granulocyte count ≥ 1,500/mm3 and platelet count ≥100,000/mm3 and hemoglobin ≥90g/dl.

Renal function: serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 60 ml/min. (based on modified Cockcroft-Gault formula).

• For all females of childbearing potential a negative serum/urine pregnancy test must be obtained within 48 hours before enrollment. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential.

Exclusion Criteria:

• Patients with prior chemotherapy or systemic anti-cancer therapy including target therapy targeting HER family members (such as erlotinib, gefitinib, cetuximab, trastuzumab, etc). Previous adjuvant or neo-adjuvant treatment for non-metastatic disease is permitted if completed ≥ 6 months before the enrollments.
• Patients with history of any other malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer).
• Patients who have brain metastasis or spinal cord compression. It is permitted if the patient has been treated with surgery and/or radiation with evidence of stable disease for at least 4 weeks.
• Patients who are at risk (in the investigator's opinion) of transmitting human immunodeficiency virus (HIV) through blood or other body fluids.
• lactating women
• Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study.
• Unwilling to write informed consent to participate in the study or unwilling to receive follow-up
• Tumor invade big vessels or close to big vessels (less than 5mm)
• Obvious cavity or necrosis formed in the tumor, Uncontrolled hypertension, Myocardial ischemia or infarction more than stage II, cardiac insufficiency. Abnormal coagulation (INR>1.5 or PT>ULN+4, or APTT>1.5 ULN), bleeding tendency or receiving coagulation therapy
• Hemoptysis, more than 2.5ml daily
• Thrombosis in 12 months, including pulmonary thrombosis, stoke, or deep venous thrombosis.
• Unhealed bone fracture or wound for long time

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gefitinib single agent; Advanced NSCLC patients with EGFR activating mutation (L858R, 19Del) received Gefitinib 250mg Qd orally until progression, intolerable toxicity or death.	Drug: Gefitinib; Patients received Gefitinib 250mg Qd orally until disease progression, intolerable toxicity or death.; Other Names: Iressa
Experimental: Gefitinib combined with chemotherapy; Gefitinib 250mg Qd combined with pemetrexed or gemcitabine plus carboplatin: Pemetrexed (500mg/m²day 1 intravenously) plus carboplatin (AUC=5,day 1,intravenously) every 21 days, Gemcitabine (1000 mg/m² days 1,d8, intravenously) plus carboplatin (AUC=5,day 1,intravenously) every 21 days	Drug: Gefitinib; Patients received Gefitinib 250mg Qd orally until disease progression, intolerable toxicity or death.; Other Names: Iressa; Drug: pemetrexed or gemcitabine plus carboplatin,; doublet chemotherapy with pemetrexed or gemcitabine plus carboplatin per 3 weeks; Other Names: Alimita or Gimza
Experimental: Gefitinib combined with antiangiogenesis; Gefetinib 250mg Qd combined with bevacizumab 7.5mg/kg per 21 days	Drug: Gefitinib; Patients received Gefitinib 250mg Qd orally until disease progression, intolerable toxicity or death.; Other Names: Iressa; Drug: bevacizumab; bevacizumab 7.5mg/kg intravenously per 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	From start of anti-cancer therapy untill progression or death	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival	evaluated in the 36th since treatment begain	36 months
side effect	toxicities related to anti-cancer therapy	8 weeks
quality of life	evaluated since treatment began	24 months

Collaborators and Investigators

• Sponsor: Caicun Zhou

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: October 10, 2016
• First Submitted That Met QC Criteria: October 10, 2016
• First Posted (Estimate): October 12, 2016

Study Record Updates

• Last Update Posted (Estimate): October 13, 2016
• Last Update Submitted That Met QC Criteria: October 11, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: NSCLC, EGFR, Bim, mutation abundance
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Folic Acid Antagonists; Gemcitabine; Carboplatin; Gefitinib; Bevacizumab; Pemetrexed
• Other Study ID Numbers: FK1408

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Share the patient characteristics, results of test, treatment and outcome.