A Study of Gefitinib With or Without Apatinib in Patients With Advanced Non-squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02824458|
Recruitment Status : Recruiting
First Posted : July 6, 2016
Last Update Posted : July 7, 2016
- Study Details
- Tabular View
- Results Submitted
- How to Read a Study Record
|Condition or disease||Intervention/treatment||Phase|
|EGFR Tyrosine Kinase Inhibitors Plus VEGFR Inhibitors||Drug: Apatinib Drug: Gefitinib Drug: Placebo||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||246 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Investigator)|
|Official Title:||A Multicenter, Randomized,Double-Blind Study of Gefitinib in Combination With Apatinib or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Advanced Non-squamous Non-Small-Cell Lung Cancer|
|Study Start Date :||June 2016|
|Estimated Primary Completion Date :||December 2023|
|Estimated Study Completion Date :||December 2023|
Experimental: Gefitinib + Apatinib
(Part A) Phase I, Open-label, Dose-escalation Study Escalating doses(500mg, 750mg, or 250mg) of Apatinib in combination with 250mg Gefitinib daily orally. Participants may continue to receive treatment until progress or intolerable.
(Part B)Multicenter, Randomized, Double-Blind Study Apatinib (dose determined from Part A of study) in combination with 250mg Gefitinib.
Patients will be treated with Apatinib, 250/500/750 mg(dose determined from Part A of study) p.o., daily
Other Name: YN968D1
Patients will be treated with Gefitinib, 250 mg p.o., daily
Other Name: Iressa
Placebo Comparator: Gefitinib + Placebo
(Part A) Not Applicable
(Part B) Placebo in combination with 250mg Gefitinib. Participants may continue to receive treatment until progress or intolerable.
Patients will be treated with Gefitinib, 250 mg p.o., daily
Other Name: Iressa
- (Part A) Determine Dose-Limiting Toxicity (DLT) of Apatinib in combination with Gefitinib [ Time Frame: 1 months ]Determine the safety, tolerability and DLTs of Apatinib in Combination With Gefitinib
- (Part A) Maximum Tolerated Dose (MTD) of Apatinib in Combination With Gefitinib [ Time Frame: 1 months ]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.
- (Part B) Progression Free Survival (PFS) [ Time Frame: Randomization to Measured Progressive Disease or Death from Any Cause (Estimated as 42 Months) ]Time from the date of enrolment until documented progression or death, whichever occurs first.
- (Part B) Overall Survival (OS) [ Time Frame: Randomization to Date of Death from Any Cause (Estimated as 50 Months) ]Time from the date of enrolment until death from any cause.
- (Part B) Objective Response Rate (ORR) [ Time Frame: Randomization to Disease Progression (Estimated as 42 Months) ]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
- (Part B) Disease Control Rate (DCR) [ Time Frame: Randomization to Disease Progression (Estimated as 42 Months) ]Achievement of objective response or stable disease for at least 6 weeks
- (Part B) Duration of Response (DoR) [ 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) ]Interval from the date of first documentation of objective response by RECIST to the date of first documented progression or relapse
- (Part B) Time to progression disease (TTPD) [ Time Frame: Randomization to Measured Progressive Disease (Estimated as 42 Months) ]Time to progression disease
- (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 [ Time Frame: Randomization to Measured Progressive Disease (Estimated as 50 Months) ]including adverse events, physical examination, vital signs (including Blood Pressure(BP)), clinical chemistry and hematology
- (Part A) Area Under roc Curve (last) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration
- (Part A) Area Under roc Curve (tau) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Area under the plasma concentration time profile after single dose from time zero to the next dose
- (Part A) Cmax [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Maximum observed plasma concentration
- (Part A) Tmax [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Time for Cmax
- (Part A) t½a [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Terminal half life
- (Part A) Ctrough [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Predose concentration during multiple dosing
- (Part A) The Apparent Clearance(CL/F) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Apparent clearance
- (Part A) The Apparent Volume of Distribution (Vd/F) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Apparent volume of distribution
- (Part A) The Metabolite to Parent Ratio of Area Under roc Curve (tau) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Metabolite to parent ratio for Area Under roc Curve (tau)
- (Part A) The Metabolite to Parent Ratio of Css,max(MRCmax) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]Metabolite to parent ratio for Cmax
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years to 70 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- ≥ 18 and ≤ 70 years of age
- Eastern Cooperative Oncology Group(ECOG)performance scale 0 - 1.
- Life expectancy of more than 3 weeks.
- Histologically or cytologic confirmed，locally advanced and/or metastatic non-squamous NSCLC of stage IIIB (unsuitable for radiotherapy) or IV or recurrent NSCLC; At least one measurable lesion according to RECIST 1.1 which has not received radiotherapy or cryotherapy.
- Documented evidence of tumor harboring an activating EGFR mutation (Example 19 del and L858R) .
- None previous chemotherapy or targeted therapy. NOTE: neoadjuvant and/or adjuvant therapy is allowed which is completed before 6 months.
- Prior radiation therapy is allowed if: 25% or less of total bone marrow had been irradiated,pelvis and chest had not been irradiated; at least 4 weeks have elapsed from the completion of radiation treatment, and the acute toxicity from radiation treatment had been recover; irradiated lesion is not including measurable lesions unless documented progress after radiation.
- Adequate hepatic, renal, heart, and hematologic functions (Absolute Neutrophil Count(ANC) ≥ 1.5×109/L, Platelet (PLT) ≥ 100×109/L, Hemoglobin(HB) ≥ 100 g/L, total bilirubin within 1.5×the upper limit of normal(ULN), and serum transaminase≤2.5×the Upper Limit Of Normal(ULN), serum creatine ≤ 1 x Upper Limit Of Normal(ULN), creatinine clearance rate ≥ 50ml/min,
- For women of child-bearing age, the pregnancy test results (serum or urine) within 7 days before enrolment must be negative. They will take appropriate methods for contraception during the study until the 8th week post the last administration of study drug. For men (previous surgical sterilization accepted), will take appropriate methods for contraception during the study until the 8th week post the last administration of study drug.
- Signed and dated informed consent. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedure.
- Squamous cell carcinoma (including adenosquamous carcinoma, undifferentiated carcinoma); small cell lung cancer (including small cell and non-small cell mixed lung cancer)
- Symptomatic brain metastases (Patients who have no symptoms and is not needed to receive therapy before 21 days may participate in this trial, but need to be confirmed by MRI\CT or venography that no hematencephalon symptom);
- Radiologically documented evidence of major blood vessel invasion or encasement by cancer; Obvious cavity or necrosis formed in the tumor.
- Uncontrolled hypertension(systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mm Hg) even though two or more than two hypotensive agents application.
- Patients who suffered from grade II or above myocardial ischemia or myocardial infarction, uncontrolled arrhythmias (including QT interval male ≥ 450 ms, female ≥ 470 ms). Grade III-IV cardiac insufficiency according to New York Heart Association(NYHA) criteria or echocardiography check: left ventricular ejection fraction (LVEF)<50%;
- History of pulmonary interstitial diseases or concurrent pulmonary interstitial diseases.
- Coagulation disfunction（INR>1.5 o rPT>Upper Limit Of Normal(ULN)+4s or Activated Partial Thromboplastin Time (APTT) >1.5 Upper Limit Of Normal(ULN)）, hemorrhagic tendency or receiving the therapy of thrombolysis or anticoagulation.
- History of clinically significant haemoptysis =< 2 months (more than 2.5ml or half of one tea spoon of fresh blood per day) prior to registration.
- History of clinically relevant major bleeding event (e.g. gastrointestinal hemorrhage, bleeding gastric ulcer, occult blood test ≥ (++), and vasculitis ;
- Within 6 months before the first treatment occurs artery / venous thromboembolic events, such as cerebral vascular accident (including transient ischemic attack(TIA), hematencephalon, cerebral infarction), deep vein thrombosis and pulmonary embolism, etc.
- Known inherited and acquired hemorrhagic and thromboplastic possibility (such as hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc.)
- Long-term untreated wounds or fractures.
- Within 4 weeks of major surgery and/or injures, fractures , ulceration.
- Significant factors that influence the ingestion and absorption of medicine, (e.g. unable swallow, chronic diarrhea and intestinal obstruction);
- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤ 6 months.
- Urine protein≥++, or 24h urine protein quantitation≥1.0g;
- Symptomatic serous effusion requiring treatment .(including hydrothorax, ascites, hydropericardium);
- Active infection need antimicrobial treatments;
- History of psychiatric drugs abuse and not be abstinent, or dysphrenia;
- Less than 4 weeks from the last clinical trial
- History or concomitant other malignancy except cured basal cell skin cancer, or carcinoma in situ of the cervix, or superficial bladder cancer;
- Administration of strong/potent cytochrome P450 (CYP)3A4 inhibitors within 7 days, or inducers within 12 days;
- Pregnant or breastfeeding women;
- Other conditions regimented at investigators' discretion.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02824458
|Contact: Hongyun Zhao||86-20-8734 email@example.com|
|Sun Yat-sen University Cancer Center||Recruiting|
|Guangzhou, Guangdong, China, 510000|
|Contact: Hongyun Zhao, PhD 86-20-8734 2482 firstname.lastname@example.org|
|Principal Investigator:||Hongyun Zhao||Sun Yat-sen University|
|Responsible Party:||Hongyun Zhao, Associate Professor, Sun Yat-sen University|
|Other Study ID Numbers:||
|First Posted:||July 6, 2016 Key Record Dates|
|Last Update Posted:||July 7, 2016|
|Last Verified:||July 2016|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Undecided|
EGFR tyrosine kinase inhibitors
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Protein Kinase Inhibitors
Molecular Mechanisms of Pharmacological Action