NOV120101 Phase 2 Study in NSCLC Patients With Aquired Resistance to 1st Generation EGFR Tyrosine Kinase Inhibitors

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a 2nd line monotherapy agent in lung adenocarcinoma patients with acquired resistance to prior EGFR tyrosine kinase inhibitors (TKIs).

Acquired resistance to prior EGFR TKIs is considered as "unmet medical need" in clinical practice. To evaluate the efficacy of NOV120101 (Poziotinib) as a second-line monotherapeutic agent, patients with acquired resistance to gefitinib or erlotinib will be enrolled in this study. Subjects will receive NOV120101 (Poziotinib) 16 mg PO once daily until disease progression or unacceptable toxicity development. Progression free survival (PFS) will be analyzed as the primary endpoint in this trial. Secondary endpoints including PFS rate at 16 weeks, ORR and DCR will also be analyzed.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female patients aged 20 years or older
2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma
3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1
4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria:

   1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs
   2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either:

      * Patients who showed complete (CR) or partial response (PR), or
      * Patients who maintained stable disease (SD) status ≥ 6 months
   3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.)
   4. No intervening systemic chemotherapy between cessation of the EGFR TKI and participation of this study
5. Patients who agree to the collection of tumor tissue specimen
6. ECOG performance status ≤ 2
7. Life expectancy of ≥ 12 weeks
8. Adequate hematological, hepatic and renal functions:

   WBC ≥ 4,000/mm3, Platelet ≥ 100,000/mm3, Serum creatinine ≤ 1.5 X ULN, AST and ALT ≤ 2.5 X ULN, Total bilirubin ≤ 1.5 X ULN
9. Patients who give written informed consent voluntarily

Exclusion Criteria:

1. Patients who receive IP within 3 days from prior treatment with gefitinib or erlotinib
2. NCI-CTCAE grade \> 1 adverse events due to treatment with gefitinib or erlotinib
3. Prior systemic chemo, immuno, hormonal and/or biological therapy except gefitinib or erlotinib within 4 weeks before IP administration
4. Acquired resistance to EGFR TKI due to conversion of adenocarcinoma into small cell lung cancer
5. Patients who received major surgery within 4 weeks before IP administration
6. Symptomatic CNS metastases (patients with radiologically and neurologically stable metastases and being off corticosteroids for at least 4 weeks are able to participate in this trial.)
7. History of other malignancies except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for ≥ 3 years and considered to be cured by investigator's judgment
8. Known pre-existing interstitial lung disease (ILD)
9. NYHA class III or IV heart failure, uncontrolled hypertension, unstable angina or myocardial infarction within 6 months, poorly controlled arrhythmia or other clinically significant cardiovascular abnormalities at investigator's discretion
10. Patients whose left ventricle ejection fraction (LVEF) is below the institutional lower limit of normal (if no lower limit of normal is defined in the site, the lower limit is 50%.)
11. Patients with known active hepatitis B, HIV infection, or other uncontrolled infectious disease
12. Clinically significant or recent acute gastrointestinal disorders with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption disorders, CTCAE grade ≥ 2 diarrhea due to any etiology)
13. Patients who cannot receive IP by mouth and be diagnosed with clinically significant gastrointestinal disorders which can prevent administration, transit or absorption of the IP
14. Pregnancy or breast-feeding
15. Women of childbearing potential (WOCBP) or men who are unwilling to use adequate contraception or be abstinent during the trial and for at least 2 months after the end of treatment
16. Patients who received other investigational products except gefitinib and erlotinib within 4 weeks before participation
17. Patients who cannot participate in this trial by investigator's judgment