| Eligibility |
Inclusion Criteria:
Participants must meet all of the following inclusion criteria to be eligible for this
study:
1. Signed written informed consent and ability to comply with the scheduled visits and
study procedures outlined in the protocol.
2. Age = 18 years, any gender.
3. Histologically or cytologically confirmed locally advanced or metastatic non-small
cell lung cancer (mainly adenocarcinoma) not suitable for curative surgery or
radiation therapy.
4. ECOG Performance Status (ECOG PS) score of 0-1. Expected survival of at least 12
weeks.
5. Prior treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI) targeted
therapy, with radiological evidence of disease progression. The last treatment before
enrollment must show radiological evidence of disease progression, intolerance to
chemotherapy toxicity, or the patient being ineligible for standard treatment or
unable to tolerate the current treatment regimen.
6. At least one measurable lesion according to the Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 criteria that has not been previously irradiated.
7. Tissue, plasma, or cytological samples collected after disease progression confirmed
by imaging following treatment with a third-generation EGFR TKI, demonstrating an
EGFR-positive gene mutation sensitive to EGFR TKI treatment (including exon 19
deletion, 21 L858R mutation, etc.), with or without T790M mutation.
8. Adequate organ and bone marrow function, with clinical laboratory test results meeting
the following criteria:
- Hematology: Neutrophils = 1.5 × 10^9/L; Platelets = 100 × 10^9/L; Hemoglobin
(Hgb) = 100 g/L;
- Liver function: Total bilirubin (TBIL) = 1.5 × upper limit of normal (ULN) (=3 ×
ULN for patients with Gilbert's syndrome); Alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) = 3 × ULN;
- Renal function: Serum creatinine (Cr) = 1.5 × ULN or creatinine clearance rate
(CCr, Cockcroft-Gault formula) = 50 mL/min; Semi-quantitative urine testing
(e.g., urine dipstick) result showing urine protein < 2+; patients with urine
protein = 2+ at baseline should undergo a 24-hour urine collection, and the
protein content in the urine within 24 hours should be < 1g;
- Coagulation function: Activated partial thromboplastin time (APTT) and
international normalized ratio (INR) both = 1.5 × ULN;
- Cardiac function: Left ventricular ejection fraction (LVEF) = 50%;
- At rest, male QTcF < 450 msec or female QTcF < 470 msec.
9. Ability to swallow oral medications.
10. Reproductive-age female patients must agree to use effective contraception throughout
the study period until 60 days after discontinuing BPI-1178 and osimertinib. Female
patients must have a negative pregnancy test result before the start of treatment or
prove the absence of pregnancy possibility. Male patients must agree to use effective
contraception throughout the study period until 120 days after discontinuing BPI-1178
and osimertinib.
11. Apart from stable Grade 2 peripheral neuropathy (CTCAE v5.0) and alopecia, any
treatment-related clinical toxicity before enrollment must have recovered to baseline
or Grade 1.
12. All patients must have sufficient mental capacity to understand the nature,
significance of the study, and risks associated with the study.
Exclusion Criteria:
Subjects with any of the following cannot be included in this study:
1. History of prior or current use of anti-tumor drugs targeting CDK4/6.
2. Individuals with allergies or a history of severe allergic reactions.
3. Tissue, plasma, or cytological samples collected after radiological confirmation of
disease progression, with testing confirming the presence of specific therapeutic
targets such as anaplastic lymphoma kinase (ALK), BRAF V600E, or retinoblastoma (Rb)
protein loss.
4. Received the last dose of anti-tumor treatment (chemotherapy, targeted therapy,
investigational drugs, immunotherapy, tumor embolization, herbal medicine for
anti-tumor purposes, etc.) within the 2 weeks preceding the start of study drug
administration.
5. Presence of third-space effusion (such as significant pleural or abdominal fluid) that
cannot be controlled by drainage or other methods.
6. Long-term use of steroids is required.
7. Unresolved hypokalemia and hypomagnesemia at the time of enrollment.
8. Meets any of the following criteria: Various clinically significant arrhythmias and
conduction abnormalities, such as atrial fibrillation, complete left bundle branch
block, third-degree heart block, second-degree heart block, PR interval > 250 msec;
various factors that may increase the risk of QT interval prolongation or arrhythmia
events, such as symptomatic heart failure - New York Heart Association (NYHA) class
II-IV, congenital long QT syndrome, Brugada syndrome, history of QT interval
prolongation (male > 470 ms, female > 480 ms) or torsades de pointes (TdP), family
history of long QT syndrome or unexplained sudden death before the age of 40, various
concomitant medications that may prolong QT interval; within the 6 months before
starting the study drug, had the following diseases, including unstable angina,
myocardial infarction, cerebrovascular accident, pulmonary embolism, etc., or
underwent cardiac revascularization surgery.
9. History of interstitial lung disease, drug-induced interstitial lung disease,
radiation pneumonitis requiring steroid treatment, or any clinically evident active
interstitial lung disease.
10. Known active infections, such as hepatitis B (HBsAg positive and hepatitis B virus
(HBV) DNA copy number = 200 IU/ml), hepatitis C, and human immunodeficiency virus
(HIV) infection.
11. Cannot be included if there has been a relapse or concurrent malignancy in the past 5
years. Cervical cancer treated with curative intent, non-melanoma skin cancer,
superficial bladder tumors (non-invasive tumors), or cancer with no recurrence for 3
years after curative treatment can be considered for inclusion.
12. History of allogeneic organ transplantation and allogeneic hematopoietic stem cell
transplantation.
13. Various factors judged by the investigator to potentially affect the intake and
absorption of BPI-1178 or osimertinib, including gastrointestinal factors (such as
uncontrolled inflammatory gastrointestinal diseases, history of abdominal fistula or
gastrointestinal perforation within 6 months, extensive small intestine resection
requiring enteral or parenteral supplementation, inability to swallow, chronic
diarrhea, intestinal obstruction, etc.).
14. Spinal cord compression, leptomeningeal metastases, or symptomatic brain metastases
cannot be included. Asymptomatic patients with brain metastases may be allowed to
participate under the following conditions: Asymptomatic brain metastases discovered
during screening, determined by the investigator not to require steroids and/or local
treatment; asymptomatic brain metastases treated with local therapy (such as
radiation) with the patient discontinuing steroids and/or antiepileptic treatment for
at least 7 days before the first administration of BPI-1178 in combination with
osimertinib.
15. Major surgery (craniotomy, thoracotomy, or laparotomy) or severe unhealed wounds,
ulcers, or fractures within the 4 weeks preceding the start of study drug
administration.
16. Local radiation therapy for symptom relief within 1 week before the first
administration of the study drug; bone marrow radiation therapy or extensive radiation
therapy exceeding 30% within 4 weeks before the first administration of the study
drug.
17. Presence of factors, according to the investigator's judgment, that may interfere with
patient participation in the trial or the assessment of study results, such as
substance abuse, alcohol addiction, medical, psychiatric illness, and social
disorders, or any factors that the investigator deems the patient unsuitable for
receiving the study drug (such as severe hypertension, diabetes, thyroid disease,
severe infection, portal hypertension, cirrhosis, etc.). Patients who were unwilling
or unable to comply with the requirements of this study protocol will be excluded.
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