| Eligibility |
Inclusion Criteria:
- Sign a written informed consent prior to any research-related procedure
- Age =18 years and = 75 years old
- ECOG PS score of 0-1
- Expected survival time = 12 weeks
- Patients with histologically or cytologically confirmed non-localizable stage
IIIB-IIIC, stage IV non-small cell lung cancer (International Association for the
Study of Lung Cancer and the Joint Committee on the American Classification of
Cancers, 8th edition). Patients with unresectable IIIB-IIIC include recurrent and
primary unresectable (surgery and radical concurrent chemoradiotherapy), and stage IV
includes primary or recurrent stage IV but without prior systemic therapy for
advanced/metastatic disease.
- Chemotherapy and chemoradiotherapy are permitted as neoadjuvant/adjuvant treatment as
long as the treatment is completed at least 12 months prior to the diagnosis of
advanced or metastatic disease
- There must be no EGFR gene-sensitive mutation, ALK gene fusion or ROS1 gene fusion in
non-squamous carcinoma
- At least one imaging measurable lesion according to the criteria for the evaluation of
the efficacy of solid tumors (RECIST version 1.1). A lesion located in the field of
exposure to previous radiotherapy is considered measurable if progression is confirmed
(within 28 days prior to the first treatment)
- Subjects with brain metastases who are asymptomatic or whose symptoms have stabilized
with local treatment are permitted to be enrolled, provided that the subject meets the
following criteria:
1. Have a measurable lesion outside the CNS.
2. No CNS symptoms or no worsening of symptoms for at least 2 weeks.
3. No glucocorticoid therapy is required, or glucocorticoid therapy has been
discontinued within 7 days prior to the first dose, or the glucocorticoid dosage
has been stable and reduced to less than 10 mg/day of prednisone (or equivalent
dose) within 7 days prior to the first dose
- Meet the following laboratory indicators (within 14 days before the first treatment):
1. Blood routine examination: absolute neutrophil count = 1.5 x 10^9/L; platelet
count = 100 x 10^9/L; hemoglobin level = 9.0 g/dL (no blood transfusion or
erythropoietin-dependent administration within 7 days).
2. Liver function: total bilirubin (TBIL) = 1.5 × upper limit of normal (ULN);
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 × ULN
in the absence of hepatic metastases; ALT or AST = 5 × ULN in the case of
patients with hepatic metastases.
3. Renal function: serum creatinine (Cr) =1.5 times ULN or Cr clearance =60 mL/min
(Cockcroft-Gault formula), and urine routine test results show urine protein
(UPRO) <2+ or 24-hour urine protein quantification <1g.
4. Coagulation: International Normalized Ratio (INR) = 1.5 times ULN or Prothrombin
Time (PT) = 1.5 times ULN within 7 days prior to study treatment; if the subject
is receiving anticoagulant therapy, as long as the PT is within the range of the
anticoagulant drug
- Heart function: the New York heart association (NYHA) classification < 3;Left
ventricular ejection fraction(LVEF)= 50%; Baseline ECG showed no PR interval
lengthened or atrioventricular block
- For female subjects of childbearing potential, a negative urine or serum pregnancy
test should be obtained within 3 days prior to receiving the first dose of study drug
(Day 1 of Cycle 1). If a negative urine pregnancy test result cannot be confirmed, a
blood pregnancy test will be requested. Females not of childbearing potential are
defined as being at least 1 year postmenopausal or having undergone surgical
sterilization or hysterectomy; if conception is at risk, all subjects (male or female)
are required to use contraception with an annual failure rate of less than 1%
throughout the treatment period up to 120 days after the end-of-treatment
administration of study drug (or 180 days after the end-of-study drug administration)
Exclusion Criteria:
- Concurrent participation in another interventional clinical study or receipt of
another investigational drug, unless participating in an observational clinical study
- Prior exposure to any anti-PD-1 or anti-PD-L1, PD-L2, CD137, CTLA-4 antibody therapy,
or any other antibody or drug specifically targeting T-cell co-stimulation or
checkpoint pathways
- Systemic therapy with proprietary Chinese medicines with anti-tumor indications or
immunomodulatory drugs (including thiopeptides, interferons, interleukins, except
those used locally for the control of hydrothorax or ascites) within 2 weeks prior to
the first dose
- Current use of oral or intravenous beta-blockers (e.g., atenolol, bisoprolol,
carvedilol, labetalol, metoprolol, nadolol, sotalol, etc.) cannot be safely switched
to a non-beta-blocker
- There are contraindications to the use of beta-blockers:
1. Hypersensitivity to any of the components of the product.
2. Bronchial asthma or risk of bronchospasm.
3. Ketoacidosis and metabolic acidosis.
4. Severe or symptomatic bradycardia (resting heart rate =55bpm), atrioventricular
block (degrees II and III), sinus block, sick sinus node syndrome.
5. Cardiogenic shock
6. Right heart insufficiency due to pulmonary hypertension.
7. Congestive heart failure (class III or IV).
8. Hypotension (systolic blood pressure < 100 mmHg).
9. Prolonged fasting.
10. Severe peripheral circulatory failure (e.g., gangrene).
11. Symptomatic peripheral arterial disease or Raynaud's syndrome, untreated
pheochromocytoma.
12. Unstable angina or variant angina.
13. Patients on rizatriptan benzoate.
14. Severe asthma or chronic obstructive pulmonary disease (COPD)
15. Uncontrolled type I or type II diabetes mellitus (glycosylated hemoglobin [HbA1C]
> 8.5 or fasting blood glucose > 160 mg/dl at screening).
16. Current use or within the last 2 years of a non-dihydropyridine calcium channel
blocker (NDCCB)
- Hepatic encephalopathy, hepatorenal syndrome or Child-Pugh class B or more severe
cirrhosis
- Tumor-related intestinal obstruction (within 3 months prior to the signing of the
informed consent) or history of inflammatory bowel disease or extensive bowel
resection (partial colectomy or extensive small bowel resection with chronic
diarrhea), Crohn's disease, ulcerative colitis
- Completion of palliative radiotherapy within 7 days prior to the first dose of study
drug
- With clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction
- History of psychotropic substance abuse or addiction
- Known hypersensitivity to the active ingredients or excipients of the study drug
- Known history of primary immunodeficiency or undergoing systemic glucocorticoid
therapy or any other form of immunosuppressive therapy
- Use of immunosuppressive drugs, excluding topical glucocorticoids by nasal,
inhalational or other routes or physiological doses of systemic glucocorticoids (i.e.,
no more than 10 mg/day of prednisone or an equivalent dose of other glucocorticoids),
or use of hormones for the prevention of contrast sensitization, within 4 weeks prior
to the first dose of study treatment
- Failure to recover adequately from any intervention-induced toxicity and/or
complications (= grade 1 or baseline, excluding weakness or alopecia) prior to
initiation of treatment
- Receipt of live attenuated influenza vaccine within 4 weeks prior to the first dose of
study treatment or planned for the duration of the study (inactivated injectable viral
vaccine against seasonal influenza is permitted up to 4 weeks prior to the first dose;
however, live attenuated influenza vaccine is not permitted)
- Major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the
first dose of study treatment or anticipation of major surgery during study treatment;
laparoscopic exploratory surgery within 2 weeks prior to the first dose of study
treatment
- Known symptomatic CNS metastases and/or carcinomatous meningitis. Subjects with
previously treated brain metastases may be enrolled in the trial if they are
clinically stable (no evidence of imaging progression for at least 4 weeks prior to
the first dose of the experimental treatment, no evidence of new brain metastases or
increase in size of pre-existing brain metastases as confirmed by repeat imaging) and
do not require steroid therapy for at least 14 days prior to the first dose of the
experimental treatment. This exception does not include carcinomatous meningitis,
which should be excluded regardless of whether it is clinically stable.
- Presence of clinically uncontrolled pleural effusion or ascites (subjects may be
recruited who do not require drainage of the effusion or who do not have a significant
increase in the effusion after 3 days of cessation of drainage)
- Patients with bone metastases at risk of paraplegia
- Known or suspected autoimmune disease or history of such disease within the last 2
years (patients with vitiligo, psoriasis, alopecia areata or Graves' disease not
requiring systemic treatment within the last 2 years, hypothyroidism requiring only
thyroid hormone replacement therapy, and type I diabetes mellitus requiring only
insulin replacement therapy may be enrolled)
- Known to have active tuberculosis.
- A history of allogeneic organ transplants and allogeneic hematopoietic stem cell
transplants is known
- Known history of human immunodeficiency virus (HIV) infection (HIV-positive)
- Known acute or chronic active hepatitis B virus (HBsAg-positive and HBVDNA viral load
=200 IU/mL or =10^3 copies/mL) or acute or chronic active hepatitis C virus (HCV
antibody-positive and HCV RNA-positive)
- Active syphilis infection requiring treatment
- Suffer from interstitial lung disease requiring steroid hormone therapy
- Serious infections that are active or poorly controlled clinically
- Severe cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism,
cerebrovascular thromboembolism); angina pectoris requiring treatment; symptomatic
peripheral vascular disease; NYHA cardiac class 3 or 4 congestive heart failure; or
uncontrolled =class 3 hypertension (diastolic blood pressure =100 mm Hg or systolic
blood pressure =160 mm Hg) despite antihypertensive treatment
- History of other primary malignancies within 5 years, except:
1. malignancies that have been in complete remission for at least 2 years prior to
enrolment and for which no other treatment was required during the study period.
2. adequately treated non-melanoma skin cancer or malignant nevus with no evidence
of disease recurrence.
3. adequately treated carcinoma in situ without evidence of disease recurrence
- Female patients who are pregnant or breastfeeding
- Other acute or chronic medical conditions, psychiatric disorders, or abnormal
laboratory test values that may result in increased risk associated with study
participation or administration of study medication, or interfere with the
interpretation of study results, and that, in the investigator's judgement, classify
the patient as ineligible for participation in this study.
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