| Eligibility |
Inclusion Criteria:
- Patients with locally advanced or metastatic NSCLC who are diagnosed by histology or
cytology and are not suitable for surgery or radiotherapy;
- Patients with EGFR sensitive mutations (including deletion of exon 19, L858R mutation
of exon 21, at least one of the above mutations) And after the last treatment
(regardless of TKI or chemotherapy), the tissue/cytology specimens collected have been
passed through a tertiary A hospital or confirmed as T790M+ by the central laboratory;
- The patient's disease progression after the first or/and second-generation EGFR-TKIs
treatment (with imaging or pathological evidence, judged by the research center);
- Life expectancy is not less than 12 weeks, ECOG(Eastern Cooperative Oncology Group,
ECOG score) is as follows:
ECOG score in the dose-escalation phase: 0~1 points, and no deterioration within 2 weeks
before enrollment, ECOG score during dose expansion stage: 0~2 points, and no deterioration
within 2 weeks before enrollment;
- According to RECIST 1.1, the patient has at least one imaging (CT/MRI) measurable
lesion. When the patient has at least one baseline Tumor lesions meet the following
requirements: accurate measurement at baseline, non-lymph node lesions with longest
diameter =10 mm, or short diameter =15 mm Of lymph node lesions. Have not received
local treatments such as radiotherapy in the past, and have not been used for research
screening biopsy (if there is only one Measurable lesions, biopsy of the lesions is
allowed, but the lesions must be performed at least 14 days after the screening biopsy
Baseline imaging examination), the measurement method is computed tomography [CT] or
magnetic resonance imaging [MRI]);
- The organ function level must meet the following requirements (no blood transfusion or
blood products, no use of hematopoietic stimulating factors, No albumin or blood
products are used): absolute neutrophil count (ANC) =1.5×109/L, platelet count (PLT)
=75×109/L, hemoglobin (Hb) =90 g/L; serum total bilirubin =1.5 times the upper limit
of normal, aspartate aminotransferase (AST) And alanine aminotransferase (ALT) =2.5
times the upper limit of normal value (if there is liver metastasis, total bilirubin
=3 times the upper limit of normal value is allowed, AST, ALT=5 times the upper limit
of normal); Creatinine clearance (Ccr) =50 ml/min (according to Cockcroft and Gault
formula); Note: If the researcher thinks it is necessary to retest (the reason for the
retest must be recorded), the above laboratory examination can only be retested once.
complex After the test meets the standard, then the laboratory parameters can be
considered qualified.
- Premenopausal women who are likely to have children must have a pregnancy test within
7 days before starting treatment, and the pregnancy test must be negative Sex, must be
non-lactating period; infertile women can not take pregnancy test and contraception,
but must meet: age 50 Over the age of, not using hormone therapy and menopause for at
least 12 months, or have been sterilized. All enrolled patients (regardless of male
(Sexual or female) should take adequate barrier contraceptive measures during the
entire treatment period and 3 months after the end of treatment;
- Volunteer to join the group and sign the informed consent, follow the trial treatment
plan and visit plan.
Exclusion Criteria:
- Have received any of the following treatments in the past:
1. First medication (first medication refers to the first use of the test drug,
hereinafter referred to as the first medication) patient use within 6 weeks Have
used nitrosoureas or mitomycin C, or have used other cytotoxic chemotherapeutics
or their drugs within 3 weeks before the first administration His anti-cancer
drugs;
2. The time from receiving any EGRF-TKI treatment to the first dose does not exceed
the 5 half-life of the drug (for example, Elotinib is not more than 8 days,
gefitinib is not more than 10 days, icotinib is not more than 2 days, and
afatinib is not more than 8 days day);
3. The time from receiving other experimental drugs or analogues to the first dose
does not exceed the drug's 5 half-life or 14 days (whichever Senior citizens);
4. The time from receiving other immune preparations to the first administration
does not exceed 28 days;
5. Major surgery (excluding vascular access establishment surgery and biopsy
surgery) within 4 weeks before the first medication;
6. The patient has received more than 30% bone marrow radiotherapy or large-area
irradiation (excluding bone transfer) within 4 weeks before the first medication.
- Have used third-generation EGFR-TKI drugs, including but not limited to osimertinib
mesylate (Teresa®), Rociletinib (CO-1686), Olmutinib (Olita®, HM61713), ASP8273,
EGF816, Ametidine mesylate Ni, Iflutinib mesylate (AST2818), Maihuatinib, Ivitinib,
etc. or the raw materials and generic drugs of these drugs;
- CYP3A4 strong inhibitors or strong inducers have been used within 7 days before the
first administration; CYP3A4 strong inhibitors or strong inducers have been used
within 14 days before the first administration Anti-tumor medicines and Chinese
medicine preparations, Chinese medicines and Chinese medicine preparations with tumor
adjuvant treatment effects, and exclusion criteria Standard 1) Other drugs with
anti-tumor activity not mentioned;
- At the beginning of the first medication, there are still unhealed toxic reactions in
the previous treatment, and "General Terminology Standards for Adverse Events (CTCAE
5.0)" If the grade exceeds grade 1 (except for hair loss), neuropathy related to
previous platinum therapy can be relaxed to grade 2.
- Spinal cord compression or brain metastasis, but the following conditions are allowed
to be selected: asymptomatic, stable disease, no need to use before the start of
research treatment Patients who have been treated with steroids for 4 weeks (if the
brain metastases have received radiotherapy or/and surgery, the radiotherapy and
surgery must be separated from the first use1 month and above before medication);
- There are any clinical evidences that suggest severe or uncontrolled systemic
diseases, for example, the researcher believes that the patient is not suitable for
participation or those that will affect patients' compliance with the research
protocol, such as patients with uncontrolled hypertension, patients with uncontrolled
diabetes, patients with coronary artery stenosis, patients with aortic dissection,
patients with aortic aneurysms, patients with active bleeding Individuals who are on
anti-infection treatment;
- Currently existing hepatitis B (hepatitis B surface antigen [HbsAg] positive or core
antibody [HbcAb] positive and HBV (hepatitis B virus DNA) positive), hepatitis C (HCV
antibody positive and HCV RNA positive), human immunodeficiency virus (HIV) infection;
- Any clinically serious gastrointestinal dysfunction that may affect the intake,
transport or absorption of the study drug, such as inability to take it orally Drugs,
uncontrollable nausea and vomiting, history of extensive gastrointestinal resection,
uncured recurrent diarrhea, atrophic gastritis (with The age of the disease is less
than 60 years old), and the proton pump inhibitors (omeprazole, lansoprazole,
pantoprazole, Rabeprazole, etc.) of stomach diseases, Crohn's disease, ulcerative
colitis;
- Meet any of the following cardiac examination or disease standards:
1. In the resting state, the average corrected QT interval (QTc) obtained from ECG
examination, QTc interval>470 msec (QTcF=QT/RR1/3, when an abnormality is found
in the first inspection, repeat the test twice within 48 hours, with an average
of 3 times result calculation);
2. Various abnormalities of heart rhythm, conduction, and resting ECG with serious
clinical significance, such as complete left bundle branch block,
? degree conduction block, ? degree conduction block, PR interval>250 msec;
3. Various factors that may increase the risk of QTc prolongation or the risk of
arrhythmia events, such as heart failure, hypokalemia, Congenital long QT
syndrome, first-degree relatives in family history have long QT syndrome or
sudden death of unknown cause under 40 years old, Are using any drugs known to
extend the QT interval;
- Left ventricular ejection fraction (LVEF) <50%;
- Have the following past history: interstitial lung disease, drug-induced interstitial
lung disease, radiation pneumonitis requiring steroid therapy;
- Acute onset or progressive, and the investigator believes that there are lung symptoms
that are not suitable for enrollment or judged that interstitial Patients with high
risk factors who are not suitable for entry into the group due to lung disease;
- Any serious or uncontrolled eye pathology, as judged by the investigator, may increase
the safety risk of the patient, such as corneal ulcers, Bulbar conjunctivitis, etc.;
- The investigator determines that the patients are not suitable for participating in
the study for other reasons (such as: the patient is unwilling to comply with the
various procedures and limitations of the study). Regulations and requirements; those
who have undergone allogeneic bone marrow transplantation; those who have other
malignant tumors in the past 5 years or at the same time [excluding cervical cancer
Cancer and treated basal cell carcinoma]; the patient's response to the active
ingredients or inactive excipients of the test drug, chemical structure and research
drug, medical history of hypersensitivity to similar drugs or similar drugs, etc.);
- At any time after the initial diagnosis, there is a confirmed EGFR 20 exon insertion
mutation.
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