A Study Comparing AC0010 and Chemotherapy in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI

A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI.

This is a phase III, open label, randomized study assessing AC0010 (300 mg, BID) versus pemetrexed/cisplatin (4-6 cycles) in patients with advanced NSCLC, who have progressed following prior therapy with EGFR-TKI.

Patients must provide a biopsy for central confirmation of T790M mutation positive. Eligible patients will be randomized (2:1) into AC0010 group or pemetrexed/cisplatin group. Patients in chemotherapy group can cross-over to AC0010 treatment when patients experience disease progression or intolerability of chemotherapy. The primary objective of the study is to compare the PFS of AC0010 and pemetrexed/cisplatin.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female, aged between 18-75 years old.
2. Histological or cytological confirmed diagnosis of locally or metastatic NSCLC (stage IIIB/IV).
3. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy.
4. Radiological proven disease progression while on first generation EGFR TKIs.
5. At least one measurable disease according to RECIST 1.1.
6. Confirmation of tumor EGFR sensitive mutation positive in previous tumor samples, including G719X, exon 19 deletion, L858R, L861Q.
7. Confirmation of tumor harboring of T790M mutation by central lab with a biopsy sample taken after failure of first generation EGFR TKIs.
8. Adequate organ function:

   * Bone marrow reserve: Absolute neutrophil count ≥1.5 ´ 109/L,. Platelet count ≥100´ 109/L , Hemoglobin≥9 g/dL
   * Liver function: Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN) or \<5 times ULN in the presence of liver metastases; Total bilirubin ≤1.5 × ULN
   * Kidney function: Creatinine ≤1.5 × ULN
9. Anti-cancer treatment prior to EGFR TKIs including chemotherapy, radiotherapy and other anti-cancer drugs for advanced stage is not allowed.
10. Resolved toxicities from prior therapy less than CTCAE grade 1 (except alopecia) and minimum 7 days of washout period from previous erlotinib, gefitinib or icotinib.
11. ECOG performance status 0 to1.
12. Life expectancy more than 3 months.
13. Patients without CNS metastases or asymptomatic patients with brain metastases. End of local therapy for brain metastases, including radiotherapy and surgery is required ≥28 days prior to beginning of screening.
14. Provision of signed informed consent.

Exclusion Criteria:

1. Undiagnosed by pathology.
2. HCV antibody positive, active hepatitis B (hepatitis B virus carrier can be recruited)
3. HIV antibody positive, other acquired immunodeficiency disease and congenital immunodeficiency disease. Patients with organ transplantation.
4. Patients received new aided/aided system therapy with palindromia in 12 months, the new aided/aieded system therapy is considered to be previous first-line treatment.
5. Condition of organ system:

   * Large field radiation or radiation field covered more than 30% bone marrow within 4 weeks of enrollment.
   * A past history of interstitial lung disease, drug-induced interstitial lung disease or other active interstitial lung disease with clinical proof
   * Idiopathic pulmonary fibrosis (IPF).
   * In the investigator opinion, any severe or uncontrolled disease, such as unstable or uncontrolled respiratory, cardiovascular, liver or kidney diseases.
   * Any unstable system disease including refractory hypertension, unstable angina pectoris, congestive heart-failure, liver and renal disease, metabolic disease.
   * Patients with other malignant tumor in 5 years (except cured cervical carcinoma in situ, Basal cell carcinomas, squamous cell carcinoma)
   * A past history of neurological disorder or mental disorder including epilepsy and dementia.
   * Patients with chronic gastrointestinal diseases, inability to swallow medication, malabsorption syndrome or previous significant bowel resection that would preclude adequate absorption of AC0010.
6. Uncontrolled pleural and pericardial effusion.
7. Patients who have used high-dose glucocorticoids or other immunosuppressive agents within 1 month prior to screening.
8. Patient with symptomatic CNS metastases.
9. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months, heart block with second degree or greater, QTcB \> 430ms（male）or \> 450ms（female）.
10. Patients receiving medication known to prolong QT interval and potent inducers and inhibitors of CYP3A4 within 4 weeks of fist dose of AC0010.
11. Patients prove 1ml plasma to site's central lab after signing informed consent and the test results show the medication of AZD9291.
12. Patients who have been registered and received the study treatment or withdrawn from the study cannot be enrolled.
13. Patients receive unrelated surgery more than 14 days prior to the screening.
14. Pregnant and lactating women.
15. Women with childbearing potential are defined as all women who are physiologically able to have a pregnancy, unless they are using an efficient contraceptive method during treatment and within 7 days after discontinuation of treatment.
16. Men who have sexual intercourse unless they use a condom during sexual intercourse during treatment and 7 days after discontinuation of treatment and do not impregnate their sexual partners during the period. Vasectomized males are also required to use condoms to prevent the transmission of drugs through semen.
17. Patients who are considered by the investigator as inappropriate to participate in the study.