Clinical trial NCT02824458: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: EGFR Tyrosine Kinase Inhibitors Plus VEGFR Inhibitors
Keywords: EGFR tyrosine kinase inhibitors
VEGFR inhibitor
NSCLC
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2016-07-06
Enrollment: 246
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: (Part A) Determine Dose-Limiting Toxicity (DLT) of Apatinib in combination with Gefitinib
timeFrame: 1 months
measure: (Part A) Maximum Tolerated Dose (MTD) of Apatinib in Combination With Gefitinib
timeFrame: 1 months
measure: (Part B) Progression Free Survival (PFS)
timeFrame: Randomization to Measured Progressive Disease or Death from Any Cause (Estimated as 42 Months)
Secondary outcomes:
measure: (Part B) Overall Survival (OS)
timeFrame: Randomization to Date of Death from Any Cause (Estimated as 50 Months)
measure: (Part B) Objective Response Rate (ORR)
timeFrame: Randomization to Disease Progression (Estimated as 42 Months)
measure: (Part B) Disease Control Rate (DCR)
timeFrame: Randomization to Disease Progression (Estimated as 42 Months)
measure: (Part B) Duration of Response (DoR)
timeFrame: 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)
measure: (Part B) Time to progression disease (TTPD)
timeFrame: Randomization to Measured Progressive Disease (Estimated as 42 Months)
measure: (Part B) Quality of Life (QoL) questionnaire
timeFrame: Baseline, End of Study (Estimated as 50 Months)
measure: (Part A + B) Safety assessment : Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: Randomization to Measured Progressive Disease (Estimated as 50 Months)
measure: (Part A) Area Under roc Curve (last)
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) Area Under roc Curve (tau)
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) Cmax
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) Tmax
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) t½a
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) Ctrough
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) The Apparent Clearance(CL/F)
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) The Apparent Volume of Distribution (Vd/F)
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) The Metabolite to Parent Ratio of Area Under roc Curve (tau)
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
measure: (Part A) The Metabolite to Parent Ratio of Css,max(MRCmax)
timeFrame: Apatinib & Gefitinib: Cycle1 Day 1 and 15
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
Study officials:
affiliation: Sun Yat-sen University
name: Hongyun Zhao
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhao H, Yao W, Min X, Gu K, Yu G, Zhang Z, Cui J, Miao L, Zhang L, Yuan X, Fang Y, Fu X, Hu C, Zhu X, Fan Y, Yu Q, Wu G, Jiang O, Du X, Liu J, Gu W, Hou Z, Wang Q, Zheng R, Zhou X, Zhang L. Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706). J Thorac Oncol. 2021 Sep;16(9):1533-1546. doi: 10.1016/j.jtho.2021.05.006. Epub 2021 May 24.
citation: Deng Z, Qin Y, Liu Y, Zhang Y, Lu Y. Role of Antiangiogenic Agents Combined With EGFR Tyrosine Kinase Inhibitors in Treatment-naive Lung Cancer: A Meta-Analysis. Clin Lung Cancer. 2021 Jan;22(1):e70-e83. doi: 10.1016/j.cllc.2020.08.005. Epub 2020 Sep 18.
citation: Zhang Z, Zhang Y, Luo F, Ma Y, Fang W, Zhan J, Li S, Yang Y, Zhao Y, Hong S, Zhou T, Zhang Y, Zhao S, Huang Y, Zhao H, Zhang L. Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer. Clin Transl Med. 2020 Jun;10(2):e33. doi: 10.1002/ctm2.33. Epub 2020 Jun 4.
citation: Zhang Z, Luo F, Zhang Y, Ma Y, Hong S, Yang Y, Fang W, Huang Y, Zhang L, Zhao H. The ACTIVE study protocol: apatinib or placebo plus gefitinib as first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (CTONG1706). Cancer Commun (Lond). 2019 Nov 7;39(1):69. doi: 10.1186/s40880-019-0414-4.