The main purpose of this study is to evaluate the safety and efficacy of Apatinib in combination with Gefitinib as compared to placebo in combination with Gefitinib in participants with stage ⅢB-IV Non-squamous non-small-cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). Safety and tolerability of Apatinib in combination with Gefitinib will be assessed in the first portion (Part A) before proceeding to the second portion of this study (Part B).
Name: Apatinib
Description: Patients will be treated with Apatinib, 250/500/750 mg(dose determined from Part A of study) p.o., dailyType: DrugGefitinib + Apatinib
Name: Gefitinib
Description: Patients will be treated with Gefitinib, 250 mg p.o., dailyType: DrugGefitinib + Apatinib Gefitinib + Placebo
Name: Placebo
Type: DrugGefitinib + Placebo
Description: Determine the safety, tolerability and DLTs of Apatinib in Combination With Gefitinib
Measure: (Part A) Determine Dose-Limiting Toxicity (DLT) of Apatinib in combination with Gefitinib Time: 1 monthsDescription: MTD was determined by testing increasing doses up to 750 mg daily (qd) on dose escalation cohorts 1 to 3 with 3 patients each. MTD reflects highest dose of drug that did not cause an unacceptable side effect (= Dose Limiting Toxicity (DLT) in more than 30% of patients; e.g., hematologic toxicities like Common Toxicity Criteria (CTC) Grade 4 Neutropenia in specific conditions, platelets < 25,000 cells/mL; specific non-hematologic/biochemical toxicities CTC Grade 3 or 4; additionally, any toxicity considered by the investigator severe enough was designated a DLT); CTC Version 2 were used.
Measure: (Part A) Maximum Tolerated Dose (MTD) of Apatinib in Combination With Gefitinib Time: 1 monthsDescription: Time from the date of enrolment until documented progression or death, whichever occurs first.
Measure: (Part B) Progression Free Survival (PFS) Time: Randomization to Measured Progressive Disease or Death from Any Cause (Estimated as 42 Months)Description: Time from the date of enrolment until death from any cause.
Measure: (Part B) Overall Survival (OS) Time: Randomization to Date of Death from Any Cause (Estimated as 50 Months)Description: Best overall response (complete remission or partial remission) across all assessment time-points according to RECIST Criteria 1.1, during the period from enrolment to termination of trial treatment
Measure: (Part B) Objective Response Rate (ORR) Time: Randomization to Disease Progression (Estimated as 42 Months)Description: Achievement of objective response or stable disease for at least 6 weeks
Measure: (Part B) Disease Control Rate (DCR) Time: Randomization to Disease Progression (Estimated as 42 Months)Description: Interval from the date of first documentation of objective response by RECIST to the date of first documented progression or relapse
Measure: (Part B) Duration of Response (DoR) Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated as 42 Months)Description: Time to progression disease
Measure: (Part B) Time to progression disease (TTPD) Time: Randomization to Measured Progressive Disease (Estimated as 42 Months)Description: including adverse events, physical examination, vital signs (including Blood Pressure(BP)), clinical chemistry and hematology
Measure: (Part A + B) Safety assessment : Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 Time: Randomization to Measured Progressive Disease (Estimated as 50 Months)Description: Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration
Measure: (Part A) Area Under roc Curve (last) Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Area under the plasma concentration time profile after single dose from time zero to the next dose
Measure: (Part A) Area Under roc Curve (tau) Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Maximum observed plasma concentration
Measure: (Part A) Cmax Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Time for Cmax
Measure: (Part A) Tmax Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Terminal half life
Measure: (Part A) t½a Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Predose concentration during multiple dosing
Measure: (Part A) Ctrough Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Apparent clearance
Measure: (Part A) The Apparent Clearance(CL/F) Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Apparent volume of distribution
Measure: (Part A) The Apparent Volume of Distribution (Vd/F) Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Metabolite to parent ratio for Area Under roc Curve (tau)
Measure: (Part A) The Metabolite to Parent Ratio of Area Under roc Curve (tau) Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Description: Metabolite to parent ratio for Cmax
Measure: (Part A) The Metabolite to Parent Ratio of Css,max(MRCmax) Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15Allocation: Randomized
Parallel Assignment
There is one SNP
A Study of Gefitinib With or Without Apatinib in Patients With Advanced Non-squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations The main purpose of this study is to evaluate the safety and efficacy of Apatinib in combination with Gefitinib as compared to placebo in combination with Gefitinib in participants with stage ⅢB-IV Non-squamous non-small-cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). --- L858R ---
5. Documented evidence of tumor harboring an activating EGFR mutation (Example 19 del and L858R) . --- L858R ---