Apatinib in the Treatment of Patients With EGFR T790M-Negative NSCLC

Study Overview
=================
Brief Summary
-----------------
This phase 2 study is designed to evaluate the safety and activity of apatinib,a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2, in combination with EGFR-TKI in NSCLC with T790M-negative after the failure of EGFR-TKI therapy.

Official Title
-----------------
A Randomized, Controlled Phase II Clinical Trial of Apatinib in Combination With EGFR-TKI Versus EGFR-TKI for Non-squamous, Non-small Cell Lung Cancer(NSCLC) With T790M-negative After the Failure of EGFR-TKI Therapy

Conditions
-----------------
Lung Diseases, Neoplasms, Respiratory Tract Diseases, Thoracic Neoplasms, Non-Small-Cell Lung

Intervention / Treatment
-----------------
* Drug: Apatinib
* Drug: EGFR-TKI


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed stage IIIB, IV non-squamous non-small cell lung cancer, with measurable lesions (the long axis of tumor lesions ≥ 10mm with CT, the short axis of lymph node lesions ≥ 15mm with CT, the lesions not receive radiotherapy, frozen or other local treatment); Patients with slow progression on first-line EGFR TKI(erlotinib / icotinib / gefitinib) treatment; No T790M mutation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; Life expectancy of more than 3 months; Adequate bone marrow function: WBC ≥ 3.0 ×10 E+9/L, neutrophil ≥ 1.5 × 10 E+9/L, platelets ≥ 80 × 10E+9/L,Hb ≥ 10.0g/dL;a total bilirubin (TBil) of ≤1.5 upper normal limitation (UNL), a alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) of ≤3UNL or ≤5UNL in case of liver metastasis, a creatinine (Cr) of ≤ 1.5 UNL; a creatinine clearance rate ≥ 50ml/min (Cockcroft-Gault); Female subjects of child-bearing potential must agree to use contraceptive measures starting 1 week before the administration of the first dose of apatinib until 8 weeks after discontinuing study drug. Male subjects must agree to use contraceptive measures during the study and 8 weeks after last dose of study drug; the participants volunteered to join this study should sign the informed consent forms, have better compliance in the follow-up; Exclusion Criteria: Squamous cell carcinoma (including adenosquamous carcinoma); Small cell lung carcinoma (including small cell carcinoma and non-small cell mixed lung carcinoma); Active brain metastases, cancerous meningitis, patients with spinal cord compression; Rapid progression of the disease or cancer invades vital organs; The distance between the tumor lesion and the large blood vessel is less than 5 mm, or there is a central tumor invading local macrovascular; obvious pulmonary cavity or tumor necrosis; Uncontrollable high blood pressure; Grade Ⅱ or above myocardial ischemia or myocardial infarction or arrhythmia control is not good,Ⅲ   Ⅳ grade cardiac insufficiency, or cardiac ultrasonography showed left ventricular ejection fraction (LVEF) <50% according to the NYHA standard; Have a history of interstitial lung disease or patients with interstitial lung disease; Coagulation abnormalities (INR> 1.5 or PT> ULN + 4s or APTT> 1.5 ULN) with bleeding tendency or undergoing thrombolytic or anticoagulant therapy; There was significant hemoptysis within 2 months prior to enrollment, or a daily hemoptysis volume is 2.5 ml or above; A clinically significant bleeding symptom or bleeding tendencies such as gastrointestinal bleeding, hemorrhagic gastric ulcer, fecal occult blood ++ and above, or vasculitis that occurred within 3 months prior to enrollment; Aneurysm / venous thrombotic events such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism; Arterial / venous thrombotic events such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism within 12 months prior to enrollment; Hereditary or acquired bleeding and thrombophilia, such as hemophilia, coagulopathy, thrombocytopenia, hypersplenism； Long-term unhealed wounds or fractures; Major surgery or severe traumatic injury, fracture or ulcer within 4 weeks prior to enrollment; Unable to swallow, chronic diarrhea or intestinal obstruction; Abdominal fistula, gastrointestinal perforation or abdominal abscess within 6 months prior to enrollment; Urinary protein ≥ ++, 24-hour urinary protein ≥ 1.0 g; Active infections require antimicrobial treatment; ALK gene abnormalities (gene fusion or mutation occurred); Pregnant or lactating women, or women unwilling or unable to take effective contraception;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: apatinib combine with EGFR-TKI<br>Every 4 weeks 1 cycle, evaluated the efficacy and safety once every 2 cycles, treat until disease progression or intolerable toxicity | Drug: Apatinib<br>* Apatinib mesylate tablets 250 mg qd po, if the patient can tolerate the toxic side effects, adjust the dose to 500mg qd po after 1 week.<br>* Other names: apatinib tablets;Drug: EGFR-TKI<br>* Imatinib tablets, 125 mg tid po; gefitinib tablets, 250 mg qd po; erlotinib tablets, 150 mg qd po<br>* Other names: Imatinib、Gefitinib or Erlotinib;|
| Active Comparator: EGFR-TKI<br>Every 4 weeks 1 cycle, evaluated the efficacy and safety once every 2 cycles, treat until disease progression or intolerable toxicity | Drug: EGFR-TKI<br>* Imatinib tablets, 125 mg tid po; gefitinib tablets, 250 mg qd po; erlotinib tablets, 150 mg qd po<br>* Other names: Imatinib、Gefitinib or Erlotinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The length of time from either the date of diagnosis or the start of treatment that half of the patients in a group of patients diagnosed with the disease are still alive. | up to 36 months | 
| Duration of response (DOR) | From first response to the date of first documented disease progression | up to 24 months | 
| Disease Control Rate (DCR) | the proportion of patients with a best overall response of CR, PR or SD in the whole body, as assessed per RECIST 1.1 by the investigator. | 24 weeks | 
| Overall response rate (ORR) | the proportion of patients with a best overall confirmed response of CR or PR in the whole body as assessed per RECIST 1.1 by the investigator | 24 weeks | 
| the quality of life (QoL) | Analysis of changes from baseline using the quality of life (QoL) instrument | up to 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
apatinib, T790 negative, NSCLC