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

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.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

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.

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• BACKGROUNDGiaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol. 2004 Mar 1;22(5):777-84. doi: 10.1200/JCO.2004.08.001. PMID 14990632
• BACKGROUNDHerbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol. 2004 Mar 1;22(5):785-94. doi: 10.1200/JCO.2004.07.215. PMID 14990633
• BACKGROUNDHerbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. doi: 10.1200/JCO.2005.02.840. Epub 2005 Jul 25. PMID 16043829