Intercalating and Maintenance Gefitinib in Combination With Chemotherapy for Advanced EGFR-mutant NSCLC

A Randomized, Open-label, Multiple-centre Study of Intercalating and Maintenance Gefitinib in Combination With Chemotherapy for Advanced NSCLC With EGFR Mutation Positive

Study Title:

Intercalating and maintenance Gefitinib in combination with chemotherapy (gemcitabine plus carboplatin) as first-line treatment for patients with advanced EGFR mutation-positive non-small cell lung cancer: A randomized, open-label, multiple-centre study.

Target population-Treatment naive EGFR mutant-positive advanced NSCLC patients.

Study Objectives - Primary Study Objective: To investigate whether intercalating and maintenance Gefitinib in combination with chemotherapy improve the Progression-Free Survival (PFS) vs. Gefitinib alone in advanced NSCLC with EGFR activating mutation.

- Secondary Study Objective： To evaluate whether intercalating and maintenance Gefitinib in combination with chemotherapy improve the Objective Response Rate (ORR), Disease control rate (DCR), Overall survival (OS), 2-year OS rate, QOL vs. Gefitinib alone.

Evaluation the safety of Intercalating and Maintenance Gefitinib in combination with chemotherapy.

- Exploratory objective: PFS of arm A vs. PFS 1 + PFS 2 of arm B Dynamic biomarker analysis using blood sample

a: The PFS 1 of arm B is the time from randomization to disease progression of 1st-line therapy or death from any cause, whichever occurs first. The PFS 2 of arm B is the time from the time of PFS 1 to disease progression of 2nd-line therapy or death from any cause, whichever occurs first.

Study Design-Prospective, open-label, randomized, multi-center study.

Study Design:

It is a two-arm, prospective, randomized, open-label, multi-center study. The study will be conducted at 5 study sites in China. West China Hospital serves as the lead site for the study. A total of 146 treatments naive EGFR mutant positive advanced NSCLC patients are planned to be enrolled into this study.

There are four periods in this study: baseline period (≤28days),main phase of treatment (Week 0-Week 16 or until disease progression),post-treatment period and follow-up until about 24 months after the last patients enrolment.

1. Baseline period: Subject will be enrolled in the study after signing informed consent form (ICF). Investigator will record patient-reported outcome, demographic data and medical history, collect the histological or cytological samples for genetic testing, conduct laboratory examination and perform imaging examination and so on. Notes: The time of imagination is effective within 4 weeks before treatment. The result of haematology, biochemistry and physical examination is effective within 7 days before treatment. Collecting blood one time at screening period (The SOP of blood collection, storage and transportation is in attachment 1).

2. Main phase of treatment: There are 8 visits during the main phase of treatment study. During the main phase of treatment, investigator conduct laboratory examination, perform imaging examination, assess the tumor status, and evaluate the patient-reported outcome and safety.

   Collecting blood one time every two cycles (The SOP of blood collection, storage and transportation is in attachment 1).

3. Post-treatment period:

   In the study group, investigators will conduct laboratory examination, perform imaging examination, assess the tumor status, and evaluate the patient-reported outcome and safety until disease progression every 8 weeks. And after disease progression investigators will enquire and record survival status of subjects every 8 weeks.

   In the control group, investigators will conduct laboratory examination, perform imaging examination, assess the tumor status, and evaluate the patient-reported outcome and safety until the first and the second disease progression every 8 weeks. In addition, the information conduct between first disease progression and second progression are optional, but should be collected if available. And after the second disease progression investigators will enquire and record survival status of subjects every 8 weeks.

   Collecting blood one time every 8 weeks until progress (for control group it will be until the first progress)

4. Follow-up period:

It will last until about 24 months after the last patients' enrolment. Accesses histological or cytological samples for EGFR testing and related drug resistant gene testing are required. In addition, collection blood is optional, but should be collected if available. All the samples collected during his/her whole life treatment are transported to West China Hospital to store and will be used for further exploratory analysis later.

All results of CT/MRI need to be burned into compact disc (CD). This study will be the first study to compare the efficacy of intercalating and maintenance gefitinib in combination with chemotherapy to gefitinib alone as first-line treatment for patients with advanced EGFR activating mutation-positive non-small cell lung cancer.

Inclusion Criteria:

• Subjects enrolled in this study are required to meet the following inclusion criteria:

  1. Patients between 18 and 75 years of age.

  2. Patients with histologically or cytologically diagnosed NSCLC,or patients with recurrent advanced NSCLC after surgery.

  3. Harboring activating mutation of EGFR,only including an exon 19 deletion or an exon 21 point mutation.

  4. Has at least one measureable lesion by RECIST 1.1

  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

  6. No prior systemic chemotherapy or targeted therapy for lung cancer before screening except neoadjuvant or adjuvant patients.

  7. Adequate organ function, including the following:

     Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.5 × 109/L,platelets ≥100 × 109/L,and hemoglobin ≥9 g/dL.

     Hepatic: bilirubin ≤1.5 times the upper limit of normal (× ULN),alkaline phosphatase (AP),aspartate transaminase (AST),and alanine transaminase (ALT) ≤3.0 × ULN (AP,AST and ALT ≤5 × ULN is acceptable if the liver has tumor involvement).

     Renal: calculated creatinine clearance (CrCl) ≥45 mL/minute based on the standard Cockcroft and Gault formula.

  8. Prior radiation therapy allowed to <25% of the bone marrow. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study enrolment.

  9. Signed informed consent document on file.

  10. Estimated life expectancy of ≥12 weeks.

  11. Patient compliance and geographic proximity that allow adequate follow up.

      Exclusion Criteria:

• Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.

  1. Known severe hypersensitivity to gefitinib.
  2. Known brain metastasis unless asymptomatic brain metastasis(without neurotic symptoms and sign) and treated with surgery and/or radiation and stable without steroid treatment for at least 2 weeks prior to the first dose of study medication.
  3. Pleural effusion or pericardiac effusion that cannot be controlled by drainage or other procedures.
  4. Previous treatment with agents targeting the HER axis.
  5. Previous systemic antitumour treatment.
  6. The last regimen of neoadjuvant or adjuvant treatment for non-metastatic disease within 12 months of study treatment.
  7. EGFR Resistance mutation (+).
  8. Surgery undertaken less than 4 weeks before the study.
  9. Inability to comply with protocol or study procedures.
  10. A serious concomitant systemic disorder that,in the opinion of the investigator，would compromise the patient's ability to complete the study.
  11. A serious cardiac condition,such as myocardial infarction within 6 months,angina,or heart disease.
  12. Second primary malignancy that is clinically detectable at the time of consideration for study enrolment.
  13. Past medical history of Interstitial Lung Disease(ILD),drug induced interstitial disease,radiation pneumonitis which required steroid treatment,or any evidence of clinically active ILD.
  14. Pre-existing idiopathic pulmonary fibrosis evidence by CT scan at baseline.
  15. Unwillingness to use contraception during the study, women who were pregnant or lactating.
  16. Being or planing to participate in other studies.