A Phase 1/2 Study of Apatinib in Combination With AP(Pemetrexed/Cisplatin) or AC(Pemetrexed/Carboplatin) as First-line Chemotherapy for Advanced Epidermal Growth Factor Receptor(EGFR) Wild Type Non-squamous Non-small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- AP or AC
- Conditions
- Lung Cancer
- Sponsor
- West China Hospital
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Objective response rate(ORR)
- Last Updated
- 8 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the safety and clinical activity of Apatinib in combination with AP(Pemetrexed/Carboplatin) or AC(Pemetrexed/Carboplatin) as first-line chemotherapy in subjects with advanced EGFR wild type non-squamous non-small cell lung cancer(NSCLC).
Detailed Description
Apatinib, an oral highly potent tyrosine-kinase inhibitor targeting VEGFR-2, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer(NSCLC). The phase I study is conducted to explore the safety, tolerability, dose-limiting toxicities(DLT), Maximum Tolerable Dose(MTD), and preliminary anti-tumor activity of Apatinib combined with platinum-based doublet chemotherapy(PB-DC) in first-line advanced EGFR wild type non-squamous non-small cell lung cancer. This will use a dose reduction trial design. A cohort of 3\~6 subjects will be enrolled at each dose level, If 0 of 3 or ≤ 1 of 6 subjects experience a DLT, the phase I trial will stop and the current dose will be considered the MTD. If 1 of 6 or more subjects experiences a DLT, dose reduce to the next dose will occur. Following completion of the dose de-escalation trial and determination of MTD, A randomized controlled trial(RCT) including 30 subjects may be enrolled to further evaluate safety, tolerability, and preliminary anti-tumor activity of Apatinib in combination with platinum-based doublet chemotherapy(PB-DC) in the same target population.
Investigators
You Lu,MD
MD
West China Hospital
Eligibility Criteria
Inclusion Criteria
- •Signed the informed consent form prior to patient entry.
- •≥ 18 and ≤ 70 years of age.
- •Histologically or pathologically confirmed non-squamous EGFR wild-type, ALK-rearrangement negative, stage IV non-small cell lung cancer(NSCLC).
- •Must have at least one measurable lesion as per RECIST 1.1 defined as a lesion that is 10mm in longest diameter or lymph node that is 15mm in short axis imaged by CT scan, prior topical treatment, such as radiotherapy or cryosurgery to the lesions is not allowed.
- •No prior systemic chemotherapy for advanced or metastatic NSCLC.
- •Eastern Cooperative Oncology Group(ECOG) performance status 0 or
- •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.
- •Adequate hepatic and renal functions: a total bilirubin (TBil) of ≤1.5 upper normal limitation (UNL), a alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) of ≤2.5 UNL or ≤5 UNL in case of liver metastasis, a creatinine (Cr) of ≤ 1.5 UNL; a creatinine clearance rate ≥ 50ml/min (Cockcroft-Gault).
- •With normal coagulation function: INR and PTT, each ≤ 1.5 x ULN.
Exclusion Criteria
- •Patients with active brain metastasis, carcinomatous meningitis, or spinal compression, or disease of brain or pia mater according to the screening test, imaging, CT or MRI tests (patients who have completed the treatment and in a stable condition 21 days before screening could be included, but brain MRI, CT or venography is required to confirm that there are no brain hemorrhage symptoms).
- •Patients with uncontrollable hypertension (systolic blood pressure\> 140 mmHg, diastolic blood pressure\> 90 mmHg, despite optimal drug therapy).
- •Patients with with grade Ⅱ myocardial ischemia or myocardial infarction, poor control of arrhythmias (including QTc interval male ≥ 450 ms, female ≥470 ms).
- •According to NYHA standard, grade Ⅲ \~ Ⅳ heart failure, or cardiac color Doppler ultrasound examination showed left ventricular ejection fraction (LVEF) \<50%.
- •Coagulation dysfunction (INR\> 1.5, PT\> ULN +4s or APTT\> 1.5 ULN), with bleeding tendency or ongoing thrombolysis or anti-blood coagulation treatment.
- •Patients treated with anticoagulation agents or Vitamin K antagonist such as Warfarin, heparin, or other similar drugs.
- •Patients who had obvious hemoptysis within 2 months before screening, or experienced daily hemoptysis with a volume more than half a tea spoon (2.5ml) or above.
- •Patients who experienced bleeding symptoms of clinical significance within 3 months before screening, or with confirmed bleeding tendency such as hemorrhage of digestive tract, hemorrhagic gastric ulcer, baseline occult blood in stool ++ and above, or vasculitis, etc.
- •Patients who manifested arterial/venous thrombus events, e.g. cerebrovascular accident (including transient ischemic attack), deep venous thrombosis and pulmonary embolism, etc., within 12 months before screening.
- •Known genetic or acquired bleeding or bleeding tendency (such as hemophilia, blood coagulation dysfunction, thrombocytopenia, and hypersplenism, etc.).
Arms & Interventions
Apatinib 750mg + AP or AC
Phase 1 study of Apatinib in combination with platinum-based doublet chemotherapy.
Intervention: AP or AC
Apatinib 750mg + AP or AC
Phase 1 study of Apatinib in combination with platinum-based doublet chemotherapy.
Intervention: Apatinib 750mg
Apatinib 500mg + AP or AC
Phase 1 study of Apatinib in combination with platinum-based doublet chemotherapy.
Intervention: AP or AC
Apatinib 500mg + AP or AC
Phase 1 study of Apatinib in combination with platinum-based doublet chemotherapy.
Intervention: Apatinib 500mg
Apatinib 250mg + AP or AC
Phase 1 study of Apatinib in combination with platinum-based doublet chemotherapy(PBDC).
Intervention: AP or AC
Apatinib 250mg + AP or AC
Phase 1 study of Apatinib in combination with platinum-based doublet chemotherapy(PBDC).
Intervention: Apatinib 250mg
Apatinib
Phase 2 study of Apatinib in combination with platinum-based doublet chemotherapy(PBDC).
Intervention: Apatinib
Apatinib
Phase 2 study of Apatinib in combination with platinum-based doublet chemotherapy(PBDC).
Intervention: AP or AC
AP or AC
Pemetrexed/Cisplatin(AP) or Pemetrexed/Carboplatin(AC), The platinum-based doublet chemotherapy, as the control group in the phase 2 study.
Intervention: AP or AC
Outcomes
Primary Outcomes
Objective response rate(ORR)
Time Frame: Up to 36 months
To determine ORR of Apatinib in combination with AP or AC in subjects with advanced EGFR wild type non-squamous non-small cell lung cancer. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
Secondary Outcomes
- median Overall Survival(Up to 36 months)
- One-year Overall Survival Rate(Up to 36 months)
- Progression-free survival (PFS)(Up to 36 months)
- Disease Control Rate (DCR)(Up to 36 months)