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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
246
Patients will be treated with Apatinib, 250/500/750 mg(dose determined from Part A of study) p.o., daily
Patients will be treated with Gefitinib, 250 mg p.o., daily
Sun Yat-sen University Cancer Center
Guangzhou, Guangdong, China
RECRUITING(Part A) Determine Dose-Limiting Toxicity (DLT) of Apatinib in combination with Gefitinib
Determine the safety, tolerability and DLTs of Apatinib in Combination With Gefitinib
Time frame: 1 months
(Part A) Maximum Tolerated Dose (MTD) of Apatinib in Combination With Gefitinib
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.
Time frame: 1 months
(Part B) Progression Free Survival (PFS)
Time from the date of enrolment until documented progression or death, whichever occurs first.
Time frame: Randomization to Measured Progressive Disease or Death from Any Cause (Estimated as 42 Months)
(Part B) Overall Survival (OS)
Time from the date of enrolment until death from any cause.
Time frame: Randomization to Date of Death from Any Cause (Estimated as 50 Months)
(Part B) Objective Response Rate (ORR)
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
Time frame: Randomization to Disease Progression (Estimated as 42 Months)
(Part B) Disease Control Rate (DCR)
Achievement of objective response or stable disease for at least 6 weeks
Time frame: Randomization to Disease Progression (Estimated as 42 Months)
(Part B) Duration of Response (DoR)
Interval from the date of first documentation of objective response by RECIST to the date of first documented progression or relapse
Time frame: 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)
(Part B) Time to progression disease (TTPD)
Time to progression disease
Time frame: Randomization to Measured Progressive Disease (Estimated as 42 Months)
(Part B) Quality of Life (QoL) questionnaire
Time frame: Baseline, End of Study (Estimated as 50 Months)
(Part A + B) Safety assessment : Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
including adverse events, physical examination, vital signs (including Blood Pressure(BP)), clinical chemistry and hematology
Time frame: Randomization to Measured Progressive Disease (Estimated as 50 Months)
(Part A) Area Under roc Curve (last)
Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) Area Under roc Curve (tau)
Area under the plasma concentration time profile after single dose from time zero to the next dose
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) Cmax
Maximum observed plasma concentration
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) Tmax
Time for Cmax
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) t½a
Terminal half life
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) Ctrough
Predose concentration during multiple dosing
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) The Apparent Clearance(CL/F)
Apparent clearance
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) The Apparent Volume of Distribution (Vd/F)
Apparent volume of distribution
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) The Metabolite to Parent Ratio of Area Under roc Curve (tau)
Metabolite to parent ratio for Area Under roc Curve (tau)
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
(Part A) The Metabolite to Parent Ratio of Css,max(MRCmax)
Metabolite to parent ratio for Cmax
Time frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
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