A Phase Ⅱ Study Assessing the Safety and Efficacy of PLB1004 in EGFR ex20ins Mutation Patients With Advanced and Metastatic Non-small Cell Lung Cancer(NSCLC)

This a three-stage study consist a Screening Phase (Day -28 to -1), a Treatment Phase (until treatment discontinuation), and a Follow-up Phase (including end of treatment visit (EOT),end of study visit(EOS), safety follow-up and survival follow-up).

Inclusion criteria

• Ability to understand and willingness to sign a written informed consent document.
• Aged at least 18 years old.
• Histologically or cytologically confirmed locally advanced or metastatic NSCLC (stage IIIB~IV).
• According to the prior treatments having received for advanced disease (platinum containing or/and immunotherapy containing systemic therapy, not more than three lines), participants were divided into two cohorts。
• Participants with EGFR ex20ins mutation.
• ECOG performance status 0 to 1.
• Life expectancy is not less than 12 weeks.
• At least one measurable lesion as defined by RECISTV1.1.
• Participants must have specific organ and bone marrow function.

Exclusion criteria

• Exclusion

• Having the anticancer therapy prior to the first dose of PLB1004 as follows:

• Any monoclonal antibodies targeting EGFR/HER2/VEGFR within 4 weeks.
• Any cytotoxic drugs or other anticancer drugs from a previous treatment regimen within 14 days.
• Any anticancer herbal medicine within 7 days
• Major surgery within 4 weeks prior to starting PLB1004 or who have not recovered from side effects of such procedure except for the biopsy of Thoracoscopy and the clinical test of Mediastinoscopy could ≤ 7 days prior to starting PLB1004..
• Radiotherapy to lung fields and whole-brain fields ≤4 weeks prior to starting PLB1004. For all other anatomic sites, radiotherapy ≤2 weeks prior to starting PLB1004 or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions is not included.
• Any anti-EGFR TKI for the EGFR ex20ins mutation.
• Any third-generation anti-EGFR TKI during the treatment having achieved a best overall response of the partial response or complete response.
• Had not recovered from the adverse events and comorbidities caused by prior Systemic chemotherapy ,surgery ,radiotherapy to ≤ Grade 1（except for hair loss and permanent radiotherapy damage ）,the neurological toxicity caused by platinum could ≤ Grade 2.
• Patients receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with PLB1004 and for the duration of the study:

• Strong inhibitors of CYP3A4
• Strong inducers of CYP3A4
• metformin a MATE transporter substrate
• Patients with spinal cord compression ,brain membrane metastasis and symptomatic central nervous system (CNS), who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study manage CNS symptoms.
• Patients with uncontrolled and symptomatic pleural effusions, peritoneal effusions and pericardial effusions within 4 weeks prior to the start of treatment with PLB1004.
• Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, indolent malignancies that currently do not require treatment, and completely resected carcinoma in situ of any type.
• Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
• Konwn positive hepatitis B (hepatitis B virus , HBV) surface antigen(HBsAg) and HBV-DNA test value≥ULN.
• known positive hepatitis C antibody(anti-HCV) and Anti-HIV(+).Note: Subjects with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.
• Having significant or uncontrolled systemic disease, including but not limited to:

• Poorly controlled hypertension (referring to systolic blood pressure>100 mmHg after treatment) .
• Ongoing or active infection.
• Keratitis or onset of ulcerative keratitis.
• Other significant disease, mental illness or laboratory abnormalities that could affect the compliance of the patient on the protocol or investigator's judgement.
• Clinically significant, uncontrolled heart disease, including but not limited to:

• Abnormal QT interval on screening electrocardiogram (ECG), defined as the average value of triplicate QTcF>470ms.
• Have significant arrhythmias such as ventricular arrhythmia, supraventricular arrhythmia which could not be controlled by drugs, nodal arrhythmia and other cardiac arrhythmias which could not be controlled by drugs, Grade≥3 of Congestive heart failure by the New York Heart Association (NYHA).
• Any factors that increase the risk of QTc interval prolongation, such as hypokalemia, genetic long QT syndrome, taking drugs that causing the QT interval prolongation.
• Medical history of deep vein thrombosis or pulmonary embolism within 6 months prior to enrolment or any of the following: Myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Or bleeding tendencies or hypercoagulable coagulopathy within 6 months prior to first dose.
• Have active digestive system disease, or major gastrointestinal surgery which may significantly affect the taking or absorption of PLB1004(such as ulcerative lesions, uncontrollable nausea, vomiting, diarrhea, and malabsorption syndrome).
• History of hypersensitivity to active or inactive excipients of PLB1004 or drugs with a similar chemical structure of class to PLB1004.
• pregnant or nursing women.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.