| Eligibility |
Inclusion Criteria:
1. Patients aged =18 years;
2. The ECOG score is 0-1, and the ECOG score of amputation patients can be widened to 2,
indicating good organ function;
3. Histologically determined CSCC with lymph node metastases or distal metastases (class
1) or locally advanced CSCC inoperable/unable to undergo radical radiotherapy (class
2).
4. Measurable tumor lesions were assessed by ultrasonography or CT within 21 days before
enrollment;
5. Estimated survival time =3 months.
6. Primary tumor site Description: squamous cell carcinoma with primary labial mucosa can
be included. Patients with primary SCC in the anogenital region (large and small
labia, penis, scrotum, and perianal region) were excluded. The primary site was the
nose, and patients were enrolled only if the investigator could definitively identify
the primary site as the skin and not the nasal mucosa extending outward into the skin.
7. Category 2 only: Cases in which the investigator considers surgery inappropriate
include: 1. Recurrent CSCC at the same location after two or more surgical operations
and unable to undergo radical resection; 2. Local infiltration of CSCC made complete
resection impossible; 3. The location of CSCC lesions is special and the operation is
difficult, which may lead to severe defects or dysfunction (such as removing all or
part of the facial structure, nose or eye, or requiring amputation); 4. Cases that are
not suitable for surgical treatment for other reasons.
8. Category 2 only: At least one of the following criteria must be met if the
investigator deems radiotherapy inappropriate: 1. The subject has received CSCC
radiation therapy such that further radiation therapy would exceed the threshold for
acceptable cumulative dose; 2. Subjects were intolerant to radiotherapy; 3. The
subject is unwilling to participate in radiotherapy; 4. Cases in which radiotherapy is
not suitable for other reasons.
9. Tumor histology: Patients with mixed histology (e.g., sarcomatoid carcinoma,
adenosquamous carcinoma) are generally not eligible for enrollment. Only when the
mixed histology type is mainly mixed basal cell carcinoma and invasive CSCC is the
main histological component, the patients can be enrolled after communication with the
investigator and approval.
10. There was at least one measurable lesion (no previous radiotherapy) according to the
response evaluation Criteria for solid tumors, version 1.1 (RECIST V1.1). For nonbody
surface lesions, accurate measurement by computed tomography (CT) or magnetic
resonance imaging (MRI) (intravenous contrast medium is preferred) at baseline showed
a long diameter =10 mm (except lymph nodes, whose short axis must be =15mm), and the
lesions were suitable for repeated accurate measurement; For body surface lesions,
calipers are required to accurately measure and show their long diameter =10 mm and
clear lesion edge for repeated and accurate measurement. If the body surface lesions
are deeply invasive lesions, CT or MRI is preferred for accurate measurement by
referring to non-body surface lesions. A lesion located in a previously irradiated
area clearly demonstrated progression that met the RECIST V1.1 criteria (surface
lesions must be confirmed as disease progression by biopsy), then the lesion was
considered measurable.
11. The subject shall consent to biopsy of the target lesion when the investigator deems
it necessary for pathological confirmation.
12. Previous antitumor therapy was required to meet the following criteria: 1. The
interval between systemic radiation therapy and the first dose of the study was =3
weeks, and the interval between local radiation therapy or bone metastases was =2
weeks. No dose of radiation was taken within 8 weeks before the first dose of this
study; 2. The interval between previous chemotherapy and previous targeted therapy and
the first administration of this study was =4 weeks, or = 5 half-lives of the drug
(whichever occurred first); 3. The interval between the first administration of
immunotherapy, biologic therapy (tumor vaccine, cytokine or tumour-controlling growth
factor), endocrine therapy, tumor embolization or other antitumor therapies including
Chinese herbal therapy with antitumor indications was =4 weeks;
13. Having full organ and bone marrow function, as defined below:
14. Blood routine: absolute neutrophil count (ANC) =1.5×109/L; Platelet count (PLT)
=90×109/L; Absolute white blood cell count (WBC) =3.0×109/L; Hemoglobin content (HGB)
=90 g/L. Note: It is not recommended to use G-CSF, GM-CSF, red blood cell transfusion,
platelet transfusion and other interventions to reach the normal range within 14 days
before examination.
15. Liver function: total bilirubin (TBIL) =1.5× upper limit of normal (ULN); If TBIL >
1.5×ULN, binding bilirubin =ULN; For subjects with liver metastases or a
history/suspicion of Gilbert's syndrome (persistent or recurrent hyperbilirubinemia,
primarily unbound bilirubin hypertrophy, with no evidence of hemolysis or liver
disease). TBIL acuities were 3 x ULN. Alanine aminotransferase (ALT) and/or aspartate
aminotransferase (AST) =2.5×ULN for subjects without liver metastases; For subjects
with liver metastases, alanine aminotransferase (ALT) and/or aspartate
aminotransferase (AST) =5×ULN.
16. Renal function: serum creatinine (Cr) =1.5×ULN, or creatinine clearance (CCr) =50
mL/min; 4) Adequate coagulation function, defined as prothrombin time (PT) and
partially activated thrombin time (APTT) =1.5× upper limit of normal (ULN); If the
subject was receiving anticoagulant therapy, the PT or INR was within the prescribed
range for the anticoagulant.
17. Female subjects of childbearing age or male subjects whose sexual partners are women
of childbearing age are required to use effective contraception throughout the
treatment period and for 6 months after the end of treatment.
18. Signed a voluntary informed consent, understanding of the study and being willing to
follow and able to complete all trial procedures.
Exclusion Criteria:
1. Received other immunomodulator therapy within 4 weeks before the first dose of this
study, or had an immune-related adverse event of grade 1 or higher within 90 days
before the first dose of this study; Or discontinuation of immunomodulator therapy due
to toxicity during previous treatment. These immunomodulators include therapeutic
vaccines, cytokine therapy, or immune checkpoint related therapies such as anti-CTLA4
and OX-40.
2. Previous antitumor therapy targeting PD-1/PD-L1 signaling pathway;
3. Participating in another interventional clinical study, except participating in an
observational (non-interventional) clinical study or being in the follow-up phase of
an interventional study;
4. Received any investigational drug within 4 weeks prior to the initial administration
of the investigational drug;
5. Use of immunosuppressive drugs within 4 weeks prior to the first administration of the
study drug, excluding
1) intranasal inhaled topical steroid treatment or topical steroid injection (e.g.,
intra-articular injection); 2) Systemic corticosteroid treatment not exceeding 10 mg/ day
of prednisone or its equivalent physiological dose;
2) Glucocorticoids as prophylaxis for allergic reactions (e.g. pre-CT)
6. The need for long-term systemic hormone or any other immunosuppressive drug therapy does
not include inhaled hormone therapy;
7. Toxicities due to previous antitumor therapy that did not return to NCI CTCAE V5.0 grade
0 or 1 or the level specified by the enrollment criteria (excluding hair loss, fatigue, or
grade 2 or less endocrine related adverse events due to radiation therapy) were present 4
weeks before the first administration of the study drug;
8. Receive live attenuated vaccine within 4 weeks prior to the first administration of the
study drug or planned during the study period;
9. Had a major surgical procedure (craniotomy, thoracotomy, or laparotomy, or otherwise as
defined by the investigator) within 4 weeks prior to the initial administration of the
study drug or had an unhealed fracture or was expected to have a major surgery during the
duration of the study. Note: Local surgical treatment of isolated lesions is acceptable for
palliative care purposes;
10. No radiographic enhanced radiographic assessment could be performed (either
iodine-enhanced CT or gadolinium MRI could be enrolled). If other conditions are met, any
contrast-enhanced radiography cannot be accepted, but comprehensive tumor evaluation can be
performed by caliper measurement, and the study can be enrolled after communication with
the investigator.
11. Other antitumor therapy (palliative radiotherapy permitted) is anticipated during the
trial treatment;
12. A history of pneumonia requiring hormonal therapy, or interstitial lung disease
(including past and present history), with the exception of local interstitial pneumonia
due to radiation therapy;
13. Known central nervous system (CNS) metastases and/or spinal cord compression and/or
cancerous meningitis,
14. History of pIA. Patients with asymptomatic brain metastases (i.e., no neurologic
symptoms, no need for glucocorticoid therapy, and no lesions > 1.5 cm) or stable symptoms
after treatment of brain metastases were eligible for participation if they met all of the
following criteria:
15. Measurable lesions outside the central nervous system; No mesencephalon, pons,
cerebellum, meninges, medulla oblongata or spinal cord metastases; Participants were
clinically stable for at least 4 weeks, had no evidence of new or expanded brain
metastases, and had stopped corticosteroid and anticonvulsant therapy for at least 14 days
prior to study treatment;
16. Active, known or suspected autoimmune disease (see Annex 1) or a history of the disease
within the previous 2 years (vitiligo, psoriasis, alopecia or Grave's disease that has not
required systematic treatment in the last 2 years, Hypothyroidism requiring only thyroid
hormone replacement therapy and type 1 diabetes requiring only insulin replacement therapy
were eligible).
17. Acute or chronic active hepatitis B [defined as hepatitis B surface antigen (HbsAg)
and/or hepatitis B core antibody (HbcAb) positive and hepatitis B virus (HBV) DNA copy
number =1×103 copies /ml or =200 copies /ml IU/ml] or positive for acute or chronic active
hepatitis C (HCV) antibody; Subjects with positive HCV antibody but negative RNA test were
allowed to enroll
18. Uncontrolled co-morbidities such as
1. Severe infection occurring within 4 weeks prior to study treatment initiation,
including but not limited to hospitalization for complications of infection,
bacteremia, or severe pneumonia; Or patients who received therapeutic oral or
intravenous antibiotics within 2 weeks before starting study treatment and who
received prophylactic antibiotics (e.g., to prevent urinary tract infection or chronic
obstructive pulmonary disease) were enrolled;
2. HIV-infected persons (HIV antibody positive);
3. History of myocarditis;
4. Symptomatic congestive heart failure (New York Heart Association Class II-IV) or
symptomatic or poorly controlled arrhythmias;
5. uncontrolled arterial hypertension (systolic blood pressure =160mmHg or diastolic
blood pressure =100 mmHg) despite standard treatment;
6. Had any arterial thromboembolic event, including myocardial infarction, unstable
angina pectoris, cerebrovascular accident, or transient ischemic attack, in the 6
months prior to enrollment;
7. require immediate intervention of esophageal or gastric varices (binding or hardening
treatment, for example) or according to the researchers' opinions or consulting
experts of gastroenterology and hepatology experts think the bleeding risk is higher,
evidence of the portal hypertension (including imaging examination showed
splenomegaly) or a history of varices bleeding of the subjects in the group of the
first 3 months must undergo endoscopic evaluation;
8. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal/varicose bleeding
event requiring blood transfusion, endoscopic or surgical treatment within 3 months
prior to study enrollment;
9. A history of deep vein thrombosis, pulmonary embolism, or any other major
thromboembolism in the 3 months prior to enrollment (implantable venous port or
catheter origin thrombosis, or superficial venous thrombosis is not considered
"severe" thromboembolism);
10. Portal vein tumor thrombus involves both the main portal vein and the left and right
branches, or the main portal vein, superior mesenteric vein and inferior vena cava
tumor thrombus;
11. Uncontrolled metabolic disorders or secondary reactions to other non-malignant organ
or systemic diseases or cancers that may lead to higher medical risks and/or
uncertainty in survival evaluation;
12. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh > 7 or more severe
cirrhosis;
13. Subjects at risk for bowel obstruction or perforation (including but not limited to a
history of acute diverticulitis, abdominal abscess, or abdominal cancer) or any of the
following: inflammatory bowel disease or extensive bowel resection (partial colectomy
or extensive bowel resection with chronic diarrhea), Crohn's disease, ulcerative
colitis, or chronic diarrhea;
14. Significant malnutrition, such as the need for intravenous nutrient supplementation;
Malnutrition was not corrected for more than 4 weeks before the first dose of study
treatment.
15. Tumor invasion of surrounding important organs (such as mediastinal great vessels,
superior vena cava, trachea, esophagus, etc.) or risk of esophagotracheal fistula or
esophagopleural fistula.
16. After esophageal or tracheal stent implantation
17. Abnormal values of other acute or chronic diseases or laboratory tests that could
increase the risk associated with study participation or study drug administration or
interfere with the interpretation of study results and, at the investigator's
discretion, classify the subject as ineligible for study participation;
18. or neurological, psychiatric/social conditions that affect compliance with study
requirements, significantly increase the risk of adverse events, or affect the
subject's ability to provide written informed consent.
19. A known history of primary immunodeficiency;
20. Known active tuberculosis or active syphilis;
21. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem
cell transplantation;
22. Patients who had a history of gastrointestinal perforation and/or fistula within 6
months prior to study enrollment and were not cured by surgery;
23. Accompanied by uncontrolled third space effusion requiring repeated drainage, such as
pleural effusion, ascites, pericardial effusion, etc. (patients who do not need drainage
effusion or have no significant increase in effusion within 3 days after stopping drainage
can be enrolled);
24. Patients who had developed other malignancies in the 5 years prior to enrollment,
except for cured cervical carcinoma in situ/cutaneous basal cell carcinoma/breast ductal
carcinoma in situ and radical prostate cancer with no detectable prostate-specific antigen
(PSA) for at least 3 years;
25. The subject is known to have had a previous severe allergic reaction to other
monoclonal antibodies or to any of the study drug preparation components; Pregnant or
lactating female subjects.
26.Patients with comorbidities that, in the judgment of the investigator, seriously
endanger the safety of the patients or interfere with the completion of the study.
|
