A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene

This is a Phase II, multicenter, single-arm, open label study of AB-106 in the Chinese patients with advanced NSCLC harboring ROS1 fusion gene.The study will be divided into two stages. First stage (Stage I) is to determine the clinical optimal dose of AB-106, which will be evaluated at two dose levels (400 mg QD and 600mg QD), and the safety, tolerability and pharmacokinetics of AB-106 will be evaluated at the same time; Second stage (Stage II) is to evaluate the efficacy and safety of AB-106 at the clinical optimal dose determined from Stage I. It is expected that 6 patients with advanced NSCLC harboring ROS1 fusion will be enrolled in the first stage. About 167 patients with ROS1 fusion will be enrolled in the second stage and divided into two treatment cohorts (Cohort A & Cohort B). It is planned to enroll about 106 ROS1-TKI treatment naïve patients in Cohort A and about 67 crizotinib pre-treated patients in Cohort B. AB-106 will be administered 600mg once daily in 21-day cycles. Patients will continue with the study treatment until progression of disease as determined by the investigator. The frequency of tumor assessments is once every 2 treatment cycles through Cycle 9, then every 3 treatment cycles through Cycle 27 and every 4 treatment cycles thereafter.

Inclusion criteria

Patients must meet all of the following criteria to be eligible for enrollment into the study:

• ≥ 18 years of age
• Histologically or cytologically confirmed locally advanced or metastatic NSCLC
• Positivity of ROS1 fusion is determined by the local qualified laboratories by using the FISH, RT-PCR or NGS assay, and the subject must provide archival tumor tissue sample for the confirmation by a sponsor-designated central laboratory
• The subject is either TKI treatment naïve(Cohort A)， or has disease progression following the treatment of crizotinib （Cohort B）
• The patient with brain metastases is either asymptomatic, or neurologically stable for at least 2 weeks prior to study entry
• Prior therapies (including chemotherapies [less than 3 lines of regimen], radiotherapy [except for palliative], or surgery) should be completed at least 2 weeks prior to study entry. The palliative radiotherapy (≤10 times) should be completed within 48 hours prior to study entry. Any acute toxic effect must be resolved to CTCAE Grade ≤1 except for alopecia
• At least one measurable target tumor lesion (as accessed by RECIST v1.1) that has not been irradiated
• ECOG Performance Status: 0 or 1
• Patient with a life expectancy ≥ 3 months based on the judgement of investigators

Adequate organ functions defined by the following criteria：

• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x ULN; or ≤5 x ULN， if there is liver metastases involvement；
• Total serum bilirubin ≤1.5 x ULN；
• Absolute neutrophil count（ANC） ≥1500/µL；
• Platelet count≥100,000/µL；
• Hemoglobin≥8.0 g/dL；
• Serum creatinine ≤2 x ULN. 11. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of the pertinent aspect of the study 12. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures 13. Male and female patients of childbearing potential must agree to sue effective methods of contraception throughout the study and for 90 days after the last dose of study medication.

Exclusion criteria

Patient presenting with any of the following criteria will not be included in the study：

• Current participation in other therapeutic investigational studies
• Previous participation in the treatment or clinical trials of other ROS1-TKIs (except for crizotinib)
• Previous participation in the treatment and clinical trials of ALK or NTRK fusion gene targeted therapies.
• Spinal cord compression unless the patient demonstrates good pain control and stabilization or recovery of neurological function, carcinomatous meningitis or leptomeningeal disease
• Patients with interstitial fibrosis or interstitial lung disease
• Any one of the following currently or in the previous 3 months: myocardial infarction, severe/unstable angina, coronary/ peripheral artery bypass graft, congestive heart failure or cerebrovascular accident including transient ischemic attack
• Ongoing cardiac dysrhythmias of NCI CTCAE (v5.0) Grade≥2, uncontrolled atrial fibrillation of any grade, or QTc interval>470 microsec
• Pregnancy or breastfeeding
• Current use of food or drugs that are known strong CYP3A inhibitors, including (but not limited to) atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit or grapefruit juice.
• Current use of drugs that are known strong CYP3A4 inducers, including (but not limited to) carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St John's Wort
• Current use of drugs that are known CYP3A4 substrates with narrow therapeutic indices, including (but not limited to) dihydroergotamine, ergotamine, pimozide, astemizole, cisapride, and terfenadine.
• Current use of drugs that are known to induce QTc prolongation
• Systematic treatment with anti-cancer therapy, including any Traditional Chinese Medicine (TCM)with anti-tumor effect indicated in the prescription information.
• Evidence of active malignancy (other than current NSCLC, non-melanoma skin cancer, in situ cervical cancer, and presumed cured prostate cancer) within the last 3 years
• Clinically active viral disease with positivity of serum HIV, HBV, HCV, RPR testing
• Difficult to swallow which may significantly impact drug absorption
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation in the judgement of investigator and sponsor