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

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ClinicalTrials.gov Identifier: NCT02824458
Recruitment Status : Recruiting
First Posted : July 6, 2016
Last Update Posted : July 7, 2016
Sponsor:
Information provided by (Responsible Party):
Hongyun Zhao, Sun Yat-sen University

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
EGFR Tyrosine Kinase Inhibitors Plus VEGFR Inhibitors Drug: Apatinib Drug: Gefitinib Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 246 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine

Drug Information available for: Gefitinib

Arm Intervention/treatment
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.

Drug: Apatinib
Patients will be treated with Apatinib, 250/500/750 mg(dose determined from Part A of study) p.o., daily
Other Name: YN968D1

Drug: Gefitinib
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.

Drug: Gefitinib
Patients will be treated with Gefitinib, 250 mg p.o., daily
Other Name: Iressa

Drug: Placebo



Primary Outcome Measures :
  1. (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

  2. (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.

  3. (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.


Secondary Outcome Measures :
  1. (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.

  2. (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

  3. (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

  4. (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

  5. (Part B) Time to progression disease (TTPD) [ Time Frame: Randomization to Measured Progressive Disease (Estimated as 42 Months) ]
    Time to progression disease

  6. (Part B) Quality of Life (QoL) questionnaire [ Time Frame: Baseline, End of Study (Estimated as 50 Months) ]
  7. (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

  8. (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

  9. (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

  10. (Part A) Cmax [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]
    Maximum observed plasma concentration

  11. (Part A) Tmax [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]
    Time for Cmax

  12. (Part A) t½a [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]
    Terminal half life

  13. (Part A) Ctrough [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]
    Predose concentration during multiple dosing

  14. (Part A) The Apparent Clearance(CL/F) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]
    Apparent clearance

  15. (Part A) The Apparent Volume of Distribution (Vd/F) [ Time Frame: Apatinib & Gefitinib: Cycle1 Day 1 and 15 ]
    Apparent volume of distribution

  16. (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)

  17. (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



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

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


Contacts
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Contact: Hongyun Zhao 86-20-8734 2482 zhaohy@sysucc.org.cn

Locations
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China, Guangdong
Sun Yat-sen University Cancer Center Recruiting
Guangzhou, Guangdong, China, 510000
Contact: Hongyun Zhao, PhD    86-20-8734 2482    zhaohy@sysucc.org.cn   
Sponsors and Collaborators
Sun Yat-sen University
Investigators
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Principal Investigator: Hongyun Zhao Sun Yat-sen University

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hongyun Zhao, Associate Professor, Sun Yat-sen University
ClinicalTrials.gov Identifier: NCT02824458     History of Changes
Other Study ID Numbers: 2016-FXY-023
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
Keywords provided by Hongyun Zhao, Sun Yat-sen University:
EGFR tyrosine kinase inhibitors
VEGFR inhibitor
NSCLC
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Apatinib
Gefitinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action