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)

It is a phase Ⅱ,open-label, single-line, Multiple cohorts, Multicenter 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).

Eligibility Criteria:
Inclusion Criteria:

1. Ability to understand and willingness to sign a written informed consent document.
2. Aged at least 18 years old.
3. Histologically or cytologically confirmed locally advanced or metastatic NSCLC (stage IIIB\~IV).
4. 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。
5. Participants with EGFR ex20ins mutation.
6. ECOG performance status 0 to 1.
7. Life expectancy is not less than 12 weeks.
8. At least one measurable lesion as defined by RECISTV1.1.
9. Participants must have specific organ and bone marrow function.

Exclusion Criteria:

* Exclusion

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

     1. Any monoclonal antibodies targeting EGFR/HER2/VEGFR within 4 weeks.
     2. Any cytotoxic drugs or other anticancer drugs from a previous treatment regimen within 14 days.
     3. Any anticancer herbal medicine within 7 days
     4. 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..
     5. 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.
     6. Any anti-EGFR TKI for the EGFR ex20ins mutation.
     7. Any third-generation anti-EGFR TKI during the treatment having achieved a best overall response of the partial response or complete response.
  2. 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.
  3. 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
  4. 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.
  5. Patients with uncontrolled and symptomatic pleural effusions, peritoneal effusions and pericardial effusions within 4 weeks prior to the start of treatment with PLB1004.
  6. 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.
  7. 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.
  8. Konwn positive hepatitis B (hepatitis B virus , HBV) surface antigen(HBsAg) and HBV-DNA test value≥ULN.
  9. 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.
  10. Having significant or uncontrolled systemic disease, including but not limited to:

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

      1. Abnormal QT interval on screening electrocardiogram (ECG), defined as the average value of triplicate QTcF\>470ms.
      2. 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).
      3. 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.
  12. 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.
  13. 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).
  14. History of hypersensitivity to active or inactive excipients of PLB1004 or drugs with a similar chemical structure of class to PLB1004.
  15. pregnant or nursing women.
  16. 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.