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).
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.
Inclusion Criteria:
- 1. Signed the informed consent form prior to patient entry.
- 2. ≥ 18 and ≤ 70 years of age.
- 3. Histologically or pathologically confirmed non-squamous EGFR wild-type,
ALK-rearrangement negative, stage IV non-small cell lung cancer(NSCLC).
- 4. 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.
- 5. No prior systemic chemotherapy for advanced or metastatic NSCLC.
- 6. Eastern Cooperative Oncology Group(ECOG) performance status 0 or 1.
- 7. Life expectancy of more than 3 months.
- 8. 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.
- 9. 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).
- 10. With normal coagulation function: INR and PTT, each ≤ 1.5 x ULN.
- 11. Adequate cardiovascular function: left ventricular ejection fraction (LVEF) ≥ 50%,
QTcF ≤ 450 msec.
- 12. Alkaline phosphatase ≤ 2.5 x ULN.
- 13. The subjects are willing to coordinate with the follow-up with good compliance.
- 14. 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.
Exclusion Criteria:
- 1. 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).
- 2. Patients with uncontrollable hypertension (systolic blood pressure> 140 mmHg,
diastolic blood pressure> 90 mmHg, despite optimal drug therapy).
- 3. Patients with with grade Ⅱ myocardial ischemia or myocardial infarction, poor
control of arrhythmias (including QTc interval male ≥ 450 ms, female ≥470 ms).
- 4. According to NYHA standard, grade Ⅲ ~ Ⅳ heart failure, or cardiac color Doppler
ultrasound examination showed left ventricular ejection fraction (LVEF) <50%.
- 5. Coagulation dysfunction (INR> 1.5, PT> ULN +4s or APTT> 1.5 ULN), with bleeding
tendency or ongoing thrombolysis or anti-blood coagulation treatment.
- 6. Patients treated with anticoagulation agents or Vitamin K antagonist such as
Warfarin, heparin, or other similar drugs.
- 7. 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.
- 8. 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.
- 9. 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.
- 10. Known genetic or acquired bleeding or bleeding tendency (such as hemophilia, blood
coagulation dysfunction, thrombocytopenia, and hypersplenism, etc.).
- 11. Patients who have unhealed wounds or fractures for a long time.
- 12. Patients who received major surgical operations or experienced severe traumatic
injuries, bone fracture, or ulcers within 4 weeks before screening.
- 13. Patients with obvious factors affecting absorption of oral drugs, such as
difficulties in swallowing, chronic diarrhea and intestinal obstruction, etc.
- 14. Occurrence of abdominal fistula, gastrointestinal perforation, or intraperitoneal
abscess within 6 months before screening.
- 15. Patients whose routine urine tests indicate that urine protein ≥ ++ or verifies
that the 24-h urine protein quantitation ≥ 1.0 g.
- 16. Patients with active hepatitis B virus or hepatitis c virus infection.
- 17. Active infection requiring antimicrobial treatment, such as antibacterial,
antifungal, or antiviral therapy.
- 18. Patients with clinical symptoms, or dropsy of serous cavity requiring surgical
treatment (including hydrothorax, ascites, and hydropericardium).
- 19. Patients who have a history of psychotropic drug abuse and are unable to break the
habit, or who have a psychogeny.
- 20. Patients who have taken part in other drug clinical tests within 4 weeks before
screening.
- 21. Prior VEGFR inhibitor treatment.
- 22. Patients who formerly suffered from or currently are complicated with other
uncured malignant tumors, except basal cell carcinoma, carcinoma in situ of cervix and
superficial bladder cancer that have been cured.
- 23. Patients who received the treatment with potent CYP3A4 inhibitors within 7 days
before screening, or potent CYP3A4 inducers within 12 days before being included.
- 24. Pregnant or lactating women, fertile patients who are unwilling or unable to take
effective contraceptive measures.
- 25. Conditions determined by investigators to possibly affect the clinical study or
determination of the study results.
