Clinical Trials /

A Study of Gefitinib With or Without Apatinib in Patients With Advanced Non-squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations

NCT02824458

Description:

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).

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study of Gefitinib With or Without Apatinib in Patients With Advanced Non-squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 2016-FXY-023
  • NCT ID: NCT02824458

Conditions

  • EGFR Tyrosine Kinase Inhibitors Plus VEGFR Inhibitors

Interventions

DrugSynonymsArms
ApatinibYN968D1Gefitinib + Apatinib
GefitinibIressaGefitinib + Apatinib
PlaceboGefitinib + Placebo

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Gefitinib + ApatinibExperimental(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.
  • Apatinib
  • Gefitinib
Gefitinib + PlaceboPlacebo Comparator(Part A) Not Applicable (Part B) Placebo in combination with 250mg Gefitinib. Participants may continue to receive treatment until progress or intolerable.
  • Gefitinib
  • Placebo

Eligibility Criteria

        Inclusion Criteria:

          1. ≥ 18 and ≤ 70 years of age

          2. Eastern Cooperative Oncology Group(ECOG)performance scale 0 - 1.

          3. Life expectancy of more than 3 weeks.

          4. 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.

          5. Documented evidence of tumor harboring an activating EGFR mutation (Example 19 del and
             L858R) .

          6. None previous chemotherapy or targeted therapy. NOTE: neoadjuvant and/or adjuvant
             therapy is allowed which is completed before 6 months.

          7. 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.

          8. 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,

          9. 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.

         10. Signed and dated informed consent. Willingness and ability to comply with scheduled
             visits, treatment plans, laboratory tests, and other study procedure.

        Exclusion Criteria:

          1. Squamous cell carcinoma (including adenosquamous carcinoma, undifferentiated
             carcinoma); small cell lung cancer (including small cell and non-small cell mixed lung
             cancer)

          2. 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);

          3. Radiologically documented evidence of major blood vessel invasion or encasement by
             cancer; Obvious cavity or necrosis formed in the tumor.

          4. Uncontrolled hypertension(systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90
             mm Hg) even though two or more than two hypotensive agents application.

          5. 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%;

          6. History of pulmonary interstitial diseases or concurrent pulmonary interstitial
             diseases.

          7. 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.

          8. 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.

          9. History of clinically relevant major bleeding event (e.g. gastrointestinal hemorrhage,
             bleeding gastric ulcer, occult blood test ≥ (++), and vasculitis ;

         10. 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.

         11. Known inherited and acquired hemorrhagic and thromboplastic possibility (such as
             hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc.)

         12. Long-term untreated wounds or fractures.

         13. Within 4 weeks of major surgery and/or injures, fractures , ulceration.

         14. Significant factors that influence the ingestion and absorption of medicine, (e.g.
             unable swallow, chronic diarrhea and intestinal obstruction);

         15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             ≤ 6 months.

         16. Urine protein≥++, or 24h urine protein quantitation≥1.0g;

         17. Symptomatic serous effusion requiring treatment .(including hydrothorax, ascites,
             hydropericardium);

         18. Active infection need antimicrobial treatments;

         19. History of psychiatric drugs abuse and not be abstinent, or dysphrenia;

         20. Less than 4 weeks from the last clinical trial

         21. History or concomitant other malignancy except cured basal cell skin cancer, or
             carcinoma in situ of the cervix, or superficial bladder cancer;

         22. Administration of strong/potent cytochrome P450 (CYP)3A4 inhibitors within 7 days, or
             inducers within 12 days;

         23. Pregnant or breastfeeding women;

         24. Other conditions regimented at investigators' discretion.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:(Part A) Determine Dose-Limiting Toxicity (DLT) of Apatinib in combination with Gefitinib
Time Frame:1 months
Safety Issue:
Description:Determine the safety, tolerability and DLTs of Apatinib in Combination With Gefitinib

Secondary Outcome Measures

Measure:(Part B) Overall Survival (OS)
Time Frame:Randomization to Date of Death from Any Cause (Estimated as 50 Months)
Safety Issue:
Description:Time from the date of enrolment until death from any cause.
Measure:(Part B) Objective Response Rate (ORR)
Time Frame:Randomization to Disease Progression (Estimated as 42 Months)
Safety Issue:
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) Disease Control Rate (DCR)
Time Frame:Randomization to Disease Progression (Estimated as 42 Months)
Safety Issue:
Description:Achievement of objective response or stable disease for at least 6 weeks
Measure:(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)
Safety Issue:
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) Time to progression disease (TTPD)
Time Frame:Randomization to Measured Progressive Disease (Estimated as 42 Months)
Safety Issue:
Description:Time to progression disease
Measure:(Part B) Quality of Life (QoL) questionnaire
Time Frame:Baseline, End of Study (Estimated as 50 Months)
Safety Issue:
Description:
Measure:(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)
Safety Issue:
Description:including adverse events, physical examination, vital signs (including Blood Pressure(BP)), clinical chemistry and hematology
Measure:(Part A) Area Under roc Curve (last)
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
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 (tau)
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Area under the plasma concentration time profile after single dose from time zero to the next dose
Measure:(Part A) Cmax
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Maximum observed plasma concentration
Measure:(Part A) Tmax
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Time for Cmax
Measure:(Part A) t½a
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Terminal half life
Measure:(Part A) Ctrough
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Predose concentration during multiple dosing
Measure:(Part A) The Apparent Clearance(CL/F)
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Apparent clearance
Measure:(Part A) The Apparent Volume of Distribution (Vd/F)
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Apparent volume of distribution
Measure:(Part A) The Metabolite to Parent Ratio of Area Under roc Curve (tau)
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Metabolite to parent ratio for Area Under roc Curve (tau)
Measure:(Part A) The Metabolite to Parent Ratio of Css,max(MRCmax)
Time Frame:Apatinib & Gefitinib: Cycle1 Day 1 and 15
Safety Issue:
Description:Metabolite to parent ratio for Cmax

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sun Yat-sen University

Trial Keywords

  • EGFR tyrosine kinase inhibitors
  • VEGFR inhibitor
  • NSCLC

Last Updated

July 6, 2016